JP5438007B2 - Inhibitors of the interaction between MDM2 and p53 - Google Patents

Description

  The present invention relates to compounds that act as inhibitors of the interaction between MDM2 and p53, in particular as modulators of the interaction between MDM2 and the proteasome, and compositions containing said compounds. The invention also provides methods for making the disclosed compounds and compositions, and methods for their use, for example as pharmaceuticals.

  p53 is a tumor suppressor protein that plays a central role in regulating the balance between cell growth and cell growth arrest / apoptosis. Under normal conditions, the half-life of p53 is very short and, as a result, the concentration of p53 in the cell is low. However, the concentration of p53 increases in response to cellular DNA damage or cellular stress (eg, oncogene activation, telomere erosion, hypoxia). This increase in p53 concentration leads to the activation of transcription of a number of genes that drive the cell either in the process of growth arrest or apoptosis. Thus, one important function of p53 is to prevent uncontrolled proliferation of damaged cells and thus protect the organism from developing cancer.

  MDM2 is an important negative regulator of p53 function. It forms a negative self-regulatory loop by binding to the amino-terminal transcriptional activation domain of p53, and therefore MDM2 inhibits p53's ability to activate transcription and proteolytically degrades the target of p53 To do both. Under normal conditions, this regulatory loop is responsible for maintaining low concentrations of p53. However, in tumors with wild-type p53, the equilibrium concentration of active p53 can be increased by antagonizing the interaction between MDM2 and p53. Other activities of MDM2 are also required for p53 degradation, as evidenced by the accumulation of ubiquitinated p53 when phosphorylation in the central domain of HDM2 is suppressed (1). The association of HDM2 with various subunits of the 26S proteasome such as S4, S5a, S6a and S6b (Non-Patent Document 2) may play a role in this process. Thus, p53 concentration can also be increased by modulating the interaction between MDM2 and the proteasome. This can lead to p53-mediated pro-apoptosis and reversion of anti-proliferative effects in these tumor cells. MDM2 antagonists may even exhibit an antiproliferative effect in tumor cells lacking functional p53.

  This positions HDM2 protein as an attractive target for the development of anti-cancer therapies.

  MDM2 is a cellular proto-oncogene. MDM2 hyperproliferation has been observed in a range of cancers. MDM2 is overexpressed in various tumors by gene amplification or increased transcription or translation. The mechanism by which MDM2 amplification promotes tumor formation is at least partially related to its interaction with p53. In cells overexpressing MDM2, the protective function of p53 is inhibited, and thus the cells are unable to respond to DNA damage or cellular stress by increasing p53 concentration, cell growth arrest and / or apoptosis To. Thus, after DNA damage and / or cell stress, cells overexpressing MDM2 continue to proliferate freely and adopt a tumorigenic phenotype. Under these conditions, disruption of the interaction of p53 and MDM2 appears to release p53 and thus allow normal signals of growth arrest and / or apoptosis to function.

In addition to inhibition of p53, MDM2 may also have a distinct function. The number of MDM2 substrates is expanding rapidly. For example, it has been shown that MDM2 interacts directly with the transcription factor E2F1 / DP1 regulated by pRb. This interaction can be crucial for the p53-independent carcinogenic activity of MDM2. One domain of E2F1 shows significant similarity to the MDM2 binding domain of p53. Since the interaction of MDM2 with both p53 and E2F1 is located at the same binding site of MDM2, MDM2 / p53 antagonists not only activate cellular p53, but are also normally deregulated in tumor cells It can be expected that E2F1 activity can also be modulated. Other important examples of MDM2 substrates are p63, p73, p21 ^{waf1. Includes cip1} .

  Also, the therapeutic efficacy of currently used DNA damaging agents (chemotherapy and radiation therapy) can be limited by the negative regulation of p53 by MDM2. Thus, if p53's MDM2 feedback inhibition is hindered, an increase in functional p53 concentration can restore therapeutic properties of these agents by restoring wild-type p53 function and / or reversing p53-related drug resistance leading to apoptosis. Effectiveness can be increased. It has been shown that combining MDM2 inhibition and DNA damaging treatment in vivo leads to a synergistic anti-tumor effect (Non-Patent Document 3).

  Thus, disruption of the interaction of MDM2 and p53 provides an approach for therapeutic intervention in tumors with wild-type or mutant p53 and may still exhibit antiproliferative effects in tumor cells lacking functional p53 In addition, tumorigenic cells can be sensitized to chemotherapy and radiation therapy.

  U.S. Patent No. 6,057,031 discloses inhibitors of the interaction between MDM2 and p53 that are particularly useful in the treatment of tumors and in enhancing the effectiveness of chemotherapy and radiation therapy.

The compound of the present invention differs structurally from the compound of Patent Document 1 by comprising an additional substituent R ²⁰ on the central phenyl ring.

  U.S. Patent No. 6,057,077 also discloses inhibitors of the interaction between MDM2 and p53 that are particularly useful in the treatment of tumors and in enhancing the effectiveness of chemotherapy and radiation therapy.

  Unexpectedly, substantial structural modification of the compound does not impair the activity of the compound. Thus, the present invention provides a more useful series of effective and potent small molecules that inhibit the interaction between MDM2 and p53 and lead to the development of new drugs.

WO 2006/032631 Specification WO 2007/107543 Specification

Blattner et al., Hypophosphorylation of Mdm2 augments p53 stability. (2002) Mol. Cell. Biol. , 22, 6170-6182 3rd Mdm2 workshop in Constance, Germany, September 2005 Vousden K.M. H. Cell, Vol. 103, 691-694, 2000)

[Detailed Description of the Invention]
The present invention provides compounds and compositions and methods for inhibiting the interaction between MDM2 and p53 to treat proliferative diseases, including tumors and cancer. Furthermore, the compounds and compositions of the invention are useful in enhancing the effectiveness of chemotherapy and radiation therapy.

  Accordingly, in one aspect, the present invention encompasses any stereochemical isomer thereof, formula (I):

[Where m is 0, 1 or 2 and when m is 0, direct bonding is intended;
n is 0, 1, 2 or 3, and when n is 0, a direct bond is intended;
p is 0 or 1, and when p is 0, a direct bond is intended;
s is 0 or 1, and when s is 0, a direct bond is intended;
t is 0 or 1, and when t is 0, a direct bond is intended;
X is C (═O) or CHR ⁸ , wherein R ⁸ is hydrogen; C _1-6 alkyl; C _3-7 cycloalkyl; —C (═O) —NR ¹⁷ R ¹⁸ ; carboxyl; aryl C _1-6 alkyloxycarbonyl; heteroaryl; heteroarylcarbonyl; heteroaryl _{C 1-6} alkyloxycarbonyl; piperazinylcarbonyl; pyrrolidinyl; _{piperidinylcarbonyl; C 1-6} alkyloxycarbonyl; hydroxy, amino, aryl and C _1-6 alkyl substituted with a substituent selected from heteroaryl; C _3-7 cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; hydroxy, hydroxy C _{1 -6} alkyl and hydroxy _{C 1-6} Arukiruoki C _1-6 piperazinylcarbonyl substituted with a substituent selected from alkyl; pyrrolidinyl substituted with a hydroxy _{C 1-6} alkyl; and _{hydroxy, C 1-6} alkyl, hydroxy _{C 1-6} alkyl, With 1 or 2 substituents selected from C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyl (dihydroxy) C _1-6 alkyl and C _1-6 alkyloxy (hydroxy) C _1-6 alkyl Selected from substituted piperidinylcarbonyl;
R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, di (C _1-6 alkyl) amino C _1-6 alkyl, aryl C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl, hydroxy Each independently selected from C _1-6 alkyl, hydroxy C _1-6 alkyl (C _1-6 alkyl) or hydroxy C _1-6 alkyl (aryl C _1-6 alkyl);

Is —CR ⁹ ═C <(and the dotted line is a bond), —C (═O) —CH <, —C (═O) —N <, —CHR ⁹ —CH <or —CHR ⁹ —. N <and each R ⁹ is independently hydrogen or C _1-6 alkyl, or R ⁹ together with one of R ² or R ²⁰ forms a direct bond;
R ¹ is hydrogen; aryl; heteroaryl; C _1-6 alkyloxycarbonyl; C _1-12 alkyl; or hydroxy, aryl, heteroaryl, amino, C _1-6 alkyloxy, mono or di (C _{1- 6} alkyl) amino, morpholinyl, piperidinyl, pyrrolidinyl, _{piperazinyl, C 1-6} alkylpiperazinyl, aryl _{C 1-6} alkyl piperazinyl, heteroaryl _{C 1-6} alkyl _{piperazinyl, C 3-7} cycloalkyl alkylpiperazino C _1-12 alkyl substituted with 1 or 2 substituents independently selected from radinyl and C _3-7 cycloalkylC _1-6 alkylpiperazinyl;
R ² and R ²⁰ are
Halo, hydroxy, cyano, nitro, carboxyl;
Polyhalo C _1-6 alkyl, polyhalo C _1-6 alkyloxy;
C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl, aryl, heteroaryl, aryl C _1-6 alkyl, heteroaryl C _1-6 alkyl, C _3-7 cycloalkyl C _1-6 alkyl , Morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C _1-6 alkyloxy, aryloxy, heteroaryloxy, C _1-6 alkylthio, arylthio, heteroarylthio, C _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, arylcarbonyl, _{heteroarylcarbonyl, C 1-6 alkyloxycarbonyl, C 3-7} cycloalkyloxycarbonyl, aryloxycarbonyl, _{heteroaryloxycarbonyl, C 1-6 alkylcarbonyloxy, C 3-7} cycloalkyl Ruboniruokishi, both arylcarbonyloxy or heteroarylcarbonyloxy (of the group, halo, hydroxy, cyano, nitro, carboxyl, amino, mono- or di _{(C 1-6} alkyl) _{amino, C 1-6} alkyl, polyhalo C One or more selected from _1-6 alkyl, aryl, heteroaryl, C _1-6 alkyloxy, C _1-6 alkylcarbonyl, C _1-6 alkyloxycarbonyl and C _1-6 alkylcarbonyloxy, preferably Are optionally and independently substituted with 1 or 2 substituents); and — (CH ₂ ) _w — (C (═O)) _y NR ²¹ R ²² [where w is 0, 1, If it is 2, 3, 4, 5 or 6 and w is 0, direct coupling is intended. ;
if y is 0 or 1, and if y is 0, a direct bond is intended;
R ²¹ and R ²² are hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkylcarbonyl and aryl C _1-6 alkylcarbonyl (all of the above groups are halo, hydroxy, amino, mono Or one or more selected from di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyloxy, aryl and heteroaryl, preferably 1 or 2 Each independently selected from, optionally and independently substituted with one substituent;
Or, R ²¹ and R ²² together with the nitrogen to which they are attached form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, any of the above groups being C _1-6 alkyl, polyhalo C _1-6 One or more selected from alkyl, C _1-6 alkyloxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, aryl C _1-6 alkyl and heteroaryl C _1-6 alkyl Or more, preferably optionally substituted independently with 1 or 2 substituents]
Are selected independently from each other;
Alternatively, R ² and R ²⁰ together with the phenyl ring to which they are attached, are halo, hydroxy, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhalo C ₁ Forms a naphthalenyl group optionally substituted with one or more, preferably 1 or 2 substituents each independently selected from _-6 alkyl, C _1-6 alkyloxy, aryl and heteroaryl Or;
Alternatively, R ² and R ^{20 taken} together are halo, hydroxy, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyl. The formula — (CH ₂ ) _b — [where b is 3, 4 or more, optionally substituted with one or more, preferably 1 or 2, substituents selected from oxy, aryl and heteroaryl Or is 5]];
Alternatively, one of R ² or R ²⁰ is as defined above and the other of R ² or R ²⁰ together with R ⁹ forms a direct bond;
R ³ is _{hydrogen; C 1-6} alkyl; _{heteroaryl; C 3-7} cycloalkyl; or hydroxy; hydroxy, amino, _{C 1-6} alkyl substituted with a substituent selected from aryl and heteroaryl C _3-7 cycloalkyl substituted with a substituent selected from amino, aryl and heteroaryl;
R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxy C _1-6 alkyl, polyhalo C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy, amino, C _{2 -6} alkenyl or C _1-6 alkyloxy; or R ⁴ and R ^{5 taken} together form a divalent group selected from methylenedioxy or ethylenedioxy;
R ⁶ is hydrogen, C _1-6 alkyloxycarbonyl or C _1-6 alkyl;
when p is 1, R ⁷ is hydrogen, arylC _1-6 alkyl, hydroxy or heteroarylC _1-6 alkyl;
Z is

Wherein R ¹⁰ or R ¹¹ is hydrogen, halo, hydroxy, amino, C _1-6 alkyl, nitro, polyhaloC _1-6 alkyl, cyano, cyano C _1-6 alkyl, tetrazolo C _1-6 alkyl, aryl, heteroaryl, aryl C _1-6 alkyl, heteroaryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, heteroaryl (hydroxy) C _1-6 alkyl, arylcarbonyl, hetero Arylcarbonyl, C _1-6 alkylcarbonyl, aryl C _1-6 alkylcarbonyl, heteroaryl C _1-6 alkylcarbonyl, C _1-6 alkyloxy, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl (hydroxy ) _{C 1-6} alkyl, aryl _{C 1-6} alkyl Carboxymethyl _{C 1-6 alkyl, C 1-6} alkyloxy _{C 1-6} alkyloxy _{C 1-6 alkyl, C 1-6}
Alkylcarbonyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl C _1-6 alkyloxy C _1-6 alkyl, hydroxy C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl C _{2 -6} alkenyl, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl, C _1-6 alkylcarbonyloxy, aminocarbonyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, hydroxy Each independently selected from carbonyl, hydroxycarbonyl C _1-6 alkyl and — (CH ₂ ) _v — (C (═O)) _r — (CHR ¹⁹ ) _u —NR ¹³ R ¹⁴ ;
Where v is 0, 1, 2, 3, 4, 5 or 6 and when v is 0, a direct bond is intended;
r is 0 or 1, and when r is 0, a direct bond is intended;
u is 0, 1, 2, 3, 4, 5 or 6 and when u is 0, direct binding is intended;
R ¹⁹ is hydrogen or C _1-6 alkyl;
R ¹³ and R ¹⁴ are hydrogen; C _1-12 alkyl; C _1-6 alkylcarbonyl; C _1-6 alkylsulfonyl; aryl C _1-6 alkylcarbonyl; C _3-7 cycloalkyl; C _3-7 cycloalkyl Carbonyl; — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ ; substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl, C _1-6 alkyloxy, aryl or heteroaryl C _1-12 alkyl; or C substituted with a substituent selected from hydroxy, C _1-6 alkyloxy, aryl, amino, aryl C _1-6 alkyl, heteroaryl or heteroaryl C _1-6 alkyl _3-7 either each independently selected from cycloalkyl; there have R ¹³ and ^{R 14,} together with the nitrogen to which they are attached, a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or _{C 1-6} alkyl, aryl _{C 1-6} alkyl, aryl _{C 1-6} alkyloxycarbonyl Forming a piperazinyl substituted with a substituent selected from heteroaryl C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 cycloalkylC _1-6 alkyl; 2, 3, 4, 5 or 6, and when k is 0, a direct bond is intended;
R ¹⁵ and R ¹⁶ are hydrogen; C _1-12 alkyl; aryl C _1-6 alkyloxycarbonyl; C _3-7 cycloalkyl; substituent selected from hydroxy, C _1-6 alkyloxy, aryl and heteroaryl _{C 1-12} alkyl is substituted in; and _{hydroxy, C 1-6} alkyloxy, aryl, aryl _{C 1-6} alkyl, substituted with a substituent selected from heteroaryl and heteroaryl _{C 1-6} alkyl Each independently selected from C _3-7 cycloalkyl; or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached, morpholinyl, piperazinyl, or C _1-6 alkyloxycarbonyl Forming piperazinyl substituted with:
R ¹² is _{hydrogen; C 1-6 alkyl; C 3-7} cycloalkyl; or hydroxy; hydroxy, _{amino, C 1-6} alkyl substituted with a substituent selected from _{C 1-6} alkyloxy and aryl C _3-7 cycloalkyl substituted with a substituent selected from amino, aryl and C _1-6 alkyloxy;
Aryl is phenyl or naphthalenyl;
Each phenyl or naphthalenyl is optionally 1, 2 or 3 substituents independently selected from halo, hydroxy, C _1-6 alkyl, amino, polyhalo C _1-6 alkyl and C _1-6 alkyloxy, respectively. And each phenyl or naphthalenyl can optionally be substituted with a divalent group selected from methylenedioxy and ethylenedioxy;
Heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;
Each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl may optionally be halo, hydroxy, C _1-6 alkyl, amino, polyhaloC _1-6 alkyl, aryl, aryl C Can be substituted with 1, 2 or 3 substituents each independently selected from _1-6 alkyl or C _1-6 alkyloxy; or
Each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl may optionally be substituted with a divalent group selected from methylenedioxy or ethylenedioxy]
A compound of
The N-oxide form, addition salt or solvate thereof are provided.

  The compounds of formula (I) may also exist in their tautomeric form. Such forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention.

  The definitions above and a number of terms used below are explained below. These terms can be used by themselves or in hybrid terms.

As used herein, halo is generic to fluoro, chloro, bromo and iodo. C _1-6 alkyl is for example 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl and the like. Linear and branched chain saturated hydrocarbon groups having the following are defined: C _1-12 alkyl is C _1-6 alkyl and its higher linear and branched chains having from 7 to 12 carbon atoms such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Includes homologues. Hydroxy C _1-6 alkyl is defined as one or more (eg 1, 2, 3 or more) hydrogens of C _1-6 alkyl as defined herein substituted with a hydroxyl substituent. Refers to said C _1-6 alkyl. PolyhaloC _1-6 alkyl and polyhaloC _1-6 alkyloxy are the same if 1, 2 or more hydrogens of C _1-6 alkyl or C _1-6 alkyloxy as defined herein are the same or Refers to said C _1-6 alkyl or C _1-6 alkyloxy, each substituted with a different halo substituent; each term polyhaloC _1-6 alkyl and polyhaloC _1-6 alkyloxy represents perhalo C _{1 1- 6} alkyl and perhalo C _1-6 alkyloxy, ie all hydrogens of C _1-6 alkyl or C _1-6 alkyloxy as defined herein are substituted with the same or different halogen substituents C _1-6 alkyl and _{C 1-6} alkyloxy also encompass, for example, trihalomethyl Define a methyl containing three identical or different halo substituents such as trifluoromethyl, or for example trihalomethyloxy represents three identical or different halos such as trifluoromethyloxy Define methyloxy containing substituents. C _2-6 alkenyl is preferably one or more double bonds, such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, Defines straight and branched chain hydrocarbon groups containing one double bond and having from 2 to 6 carbon atoms. C _3-7 cycloalkyl is an aliphatic saturated and unsaturated hydrocarbon group having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like. Include. Preferably, C _3-7 cycloalkyl includes an aliphatic saturated hydrocarbon group having from 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

  The term “addition salt” means that the compound of formula (I) is an amine, an alkali metal base and an alkaline earth metal base, or an organic or inorganic base such as a quaternary ammonium base, or an inorganic acid, sulfonic acid, carboxylic acid Or a salt that can be formed with an organic or inorganic acid such as a phosphorus-containing acid.

  The term “addition salt” further comprises pharmaceutically acceptable salts, metal complexes and salts thereof that the compounds of formula (I) are capable of forming.

  The term “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid or base addition salt. The pharmaceutically acceptable acid or base addition salts mentioned above are the therapeutically active non-toxic acid and non-toxic base addition salt forms that the compounds of formula (I) can form. Is meant to comprise. Compounds of formula (I) having basic properties can be converted into their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Suitable acids are, for example, halohydro acids, eg inorganic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar acids; or eg acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid , Oxalic acid, malonic acid, succinic acid (ie butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid Organic acids such as salicylic acid, p-aminosalicylic acid, pamoic acid and similar acids.

  Compounds of formula (I) having acidic properties can be converted to their pharmaceutically acceptable base addition salts by treating the acid form with a suitable organic or inorganic base. Suitable base salt forms include, for example, salts with organic bases such as ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts such as benzathine, N-methyl-D-glucamine , Hydrabamine salts, and salts with amino acids such as arginine, lysine and the like.

  Preferably, the term addition salt means a pharmaceutically acceptable acid or base addition salt.

  The term “metal complex” means a complex formed between a compound of formula (I) and one or more organic or inorganic metal salt (s). Examples of the organic or inorganic salts include the second main group (for example, magnesium or calcium salt), the third or fourth main group (for example, aluminum, tin, lead) of the periodic table, and, for example, chromium, manganese, iron, cobalt, 1st to 8th transition group metal halides of the periodic table such as nickel, copper, zinc, etc., nitrates, sulfates, phosphates, acetates, trifluoroacetates, trichloroacetates, propionates, Tartrate salts, sulfonate salts such as methyl sulfonate, 4-methylphenyl sulfonate, salicylate, benzoate and the like.

  As used herein, the term “stereoisomer of a compound of formula (I)” is composed of the same atoms bonded by the same sequence of bonds that a compound of formula (I) may have. Define all possible compounds with different three-dimensional structures that are but not compatible. Unless otherwise stated or indicated, the chemical designation of a compound includes a mixture of all possible stereoisomers that the compound may have. Said mixture may contain all diastereomers and / or enantiomers of the basic molecular structure of said compound. All stereoisomers of the compounds of formula (I), both in pure form or in admixture with each other, are intended to be included within the scope of the present invention.

  Of particular interest are compounds of formula (I) that are stereochemically pure.

  Pure stereoisomers of the compounds and intermediates mentioned herein are isomers substantially free of other enantiomers or diastereomers of the same basic molecular structure of the compound or intermediate. It is defined as In particular, the term “stereochemically pure” means a minimum of 80% (ie, a minimum of 90% of one isomer and a maximum of 10% of other possible isomers) of stereoisomer excess to 100% stereo A compound or intermediate having an isomeric excess (ie, 100% of one isomer and no other), more preferably having a stereoisomeric excess of 90% to 100%, even more preferably 94% to 100% And most preferably relates to compounds or intermediates having a stereoisomer excess of 97% to 100%. The terms “enantiomerically pure” and “diastereomerically pure” are understood in a similar manner, but then taking into account the enantiomeric excess, diastereomeric excess, respectively, in the mixture in question. Should.

  The N-oxide forms of the compounds of formula (I) are those in which one or several tertiary nitrogen atoms are N-oxidized with one or more of the so-called N-oxides, in particular piperidine, piperazine or piperazinyl nitrogen. It is meant to comprise a compound of formula (I) that has been oxidized to the N-oxide.

  A compound of formula (I) can be converted to the corresponding N-oxide form according to procedures known in the art for converting trivalent nitrogen to its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides include, for example, benzene carbohydrate, among others. Peroxy acids or halo-substituted benzene carboperoxy acids such as 3-chlorobenzene carboperoxy acid, peroxoalkanoic acids such as peroxoacetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide can be included. Suitable solvents are, for example, water, lower alcohols such as ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

  Compounds of formula (I) may form solvates with, for example, water (ie hydrates) or universal organic solvents such as alcohols. As used herein, the term “solvate” means a physical association of a compound of formula (I) with one or more solvent molecules, as well as salts thereof. This physical association involves varying degrees of ionic and other bonds, including hydrogen bonds. In certain instances, a solvate can be capable of isolation if, for example, one or more solvent molecules are incorporated into the crystalline lattice of the crystalline solid. The term “solvate” is intended to encompass both solution phase and isolatable solvates. Non-limiting examples of suitable solvates include hydrates, ethanol solvates, methanol solvates and the like.

  In addition, the compounds of the present invention can be amorphous or can have one or more crystalline polymorphs, the forms of which are intended to be included within the scope of the present invention. doing.

The present invention includes any isotopes of atoms present in the compounds of the invention. For example, hydrogen isotopes include tritium and deuterium, and carbon isotopes include ¹³ C and ¹⁴ C.

Whenever used below, the term “compound of formula (I)” refers to the N-oxide form, acid or base addition salt of said compound of formula (I), in particular a pharmaceutically acceptable acid or Base addition salts, solvates and all stereoisomers are also meant to be included.

The first group of interesting compounds (referred to herein as group “G1”) has the following restrictions: a) X is C (═O) or CHR ⁸ where R ⁸ is hydrogen C _1-6 alkyl; C _3-7 cycloalkyl; aminocarbonyl; mono or di (C _1-6 alkyl) aminocarbonyl; carboxyl; aryl C _1-6 alkyloxycarbonyl; heteroaryl C _1-6 alkyloxycarbonyl ; C _1-6 alkyloxycarbonyl; hydroxy, amino, aryl and C _1-6 alkyl substituted with a substituent selected from heteroaryl; or, hydroxy, amino, substituents selected from aryl and heteroaryl Selected from C _3-7 cycloalkyl substituted with
b) R ¹ is hydrogen; aryl; heteroaryl; C _1-12 alkyl; or hydroxy, aryl, heteroaryl, amino, C _1-6 alkyloxy, mono or di (C _1-6 alkyl) amino, morpholinyl , piperidinyl, pyrrolidinyl, _{piperazinyl, C 1-6} alkylpiperazinyl, aryl _{C 1-6} alkyl piperazinyl, heteroaryl _{C 1-6} alkyl _{piperazinyl, C 3-7} cycloalkyl piperazinyl and _{C 3-} C _1-12 alkyl substituted with 1 or 2 substituents independently selected from ₇ cycloalkyl C _1-6 alkyl piperazinyl;
c) ^{R 3} is _{hydrogen; C 1-6 alkyl; C 3-7} cycloalkyl; hydroxy, amino, _{C 1-6} alkyl substituted with a substituent selected from aryl and heteroaryl; or hydroxy, amino C _3-7 cycloalkyl substituted with a substituent selected from aryl, heteroaryl;
d) R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxy C _1-6 alkyl, polyhalo C _1-6 alkyl, hydroxy, amino, C _2-6 alkenyl or C _{1- In} particular, R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, polyhaloC _1-6 alkyl, hydroxy, amino or C _1-6 alkyloxy;
e) R ⁴ and R ⁵ together form a divalent group selected from methylenedioxy or ethylenedioxy;
f) R ⁶ is hydrogen or C _1-6 alkyl;
g) when p is 1, R ⁷ is hydrogen, aryl C _1-6 alkyl or heteroaryl C _1-6 alkyl;
h) Z is a group selected from (a-1), (a-2), (a-3), (a-4) and (a-5);
^{i) R 10} or ^{R 11} is hydrogen; hydroxyl; _{amino; C 1-6} alkyl; nitro; polyhaloC _{C 1-6} alkyl, cyano, _{cyano-C 1-6} alkyl; tetrazolo _{C 1-6} alkyl; aryl; heteroaryl Aryl C _1-6 alkyl; Heteroaryl C _1-6 alkyl; Aryl (hydroxy) C _1-6 alkyl; Heteroaryl (hydroxy) C _1-6 alkyl; Arylcarbonyl; Heteroarylcarbonyl; Aryl C _1-6 alkyl Heteroaryl C _1-6 alkylcarbonyl; C _1-6 alkyloxy; C _1-6 alkyloxy C _1-6 alkyl; C _1-6 alkyloxycarbonyl; C _1-6 alkylcarbonyloxy; aminocarbonyl; C _1-6 alkyl; amino C _1-6 Alkyl; hydroxycarbonyl; hydroxycarbonyl C _1-6 alkyl and — (CH ₂ ) _v — (C (═O)) _r — (CH ₂ ) _u —NR ¹³ R ¹⁴ each independently selected;
j) R ¹³ and R ¹⁴ are hydrogen; C _1-12 alkyl; C _3-7 cycloalkyl; — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ ; hydroxy, C _1-6 alkyloxy, aryl and heteroaryl C _1-12 alkyl substituted with a selected substituent; or selected from hydroxy, C _1-6 alkyloxy, aryl, aryl C _1-6 alkyl, heteroaryl and heteroaryl C _1-6 alkyl Each independently selected from C _3-7 cycloalkyl substituted with a substituent;
k) R ¹³ and R ¹⁴ together with the nitrogen to which they are attached, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or C _1-6 alkyl, aryl C _1-6 alkyl, heteroaryl C _1-6 Forming piperazinyl substituted with a substituent selected from alkyl, C _3-7 cycloalkyl and C _3-7 cycloalkylC _1-6 alkyl;
^{l) R 15} and ^{R 16} is _{hydrogen; C 1-12 alkyl; C 3-7} cycloalkyl; _{hydroxy, C 1-6 C 1} to alkyloxy, substituted with a substituent selected from aryl and heteroaryl _-12 alkyl; and C _3-7 cycloalkyl substituted with a substituent selected from hydroxy, C _1-6 alkyloxy, aryl, aryl C _1-6 alkyl, heteroaryl and heteroaryl C _1-6 alkyl A substituent wherein R ¹⁵ and R ¹⁶ are each selected from hydrogen; C _1-6 alkyl; C _3-7 cycloalkyl; hydroxy, C _1-6 alkyloxy, aryl and heteroaryl in _{C 1-12} alkyl is substituted; and _{hydroxy, C 1-6} alkyloxy Aryl, aryl C _1-6 alkyl, each independently selected from C _3-7 cycloalkyl substituted with a substituent selected from heteroaryl and heteroaryl C _1-6 alkyl;
m) heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl is halo, hydroxy, Can be optionally substituted with 1, 2 or 3 substituents independently selected from C _1-6 alkyl, amino, polyhaloC _1-6 alkyl and C _1-6 alkyloxy; and n) Each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl is optionally a divalent group selected from methylenedioxy or ethylenedioxy It can be substituted,
Consisting of a compound of formula (I), wherein any one or more or all of

A second group of interesting compounds (referred to herein as group “G2”) has the following restrictions: a) n is 0, 1 or 2;
b) p is 0;
c) X is C (= O) or CHR ^8, preferably CHR ^8, wherein the hydrogen ^{R 8} is, aminocarbonyl, aryl _{C 1-6} alkyloxycarbonyl is substituted with, or hydroxy _{C 1-6} Is alkyl;
d)

Is —CR ⁹ ═C <or —CHR ⁹ —CH <;
e) ^{R 1} is _{hydrogen, C 1-12} alkyl, or be a _{C 1-12} alkyl substituted with heteroaryl;
f) R ³ is hydrogen or C _1-6 alkyl;
g) R ⁴ and R ⁵ are each independently hydrogen, halo or C _1-6 alkyloxy;
h) Z is a group selected from (a-1), (a-2), (a-3) and (a-4);
i) R ¹⁰ or R ¹¹ is hydrogen, hydroxy, amino, C _1-6 alkyl, nitro, polyhaloC _1-6 alkyl, cyano, aryl, aryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl , Arylcarbonyl, C _1-6 alkyloxy, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, hydroxycarbonyl And — (CH ₂ ) _v — (C (═O)) _r — (CH ₂ ) _u —NR ¹³ R ¹⁴ each independently selected;
j) v is 0 or 1;
k) r is 0 or 1;
l) u is 0;
m) R ¹³ and R ¹⁴ are each independently selected from hydrogen, C _1-6 alkyl, — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ , and C _1-12 alkyl substituted with hydroxy; n) R ¹³ and R ¹⁴ together with the nitrogen to which they are attached can form pyrrolidinyl;
o) k is 2;
p) R ¹⁵ and R ¹⁶ are each independently C _1-6 alkyl;
q) aryl is phenyl or phenyl substituted with halo; and r) heteroaryl is pyridinyl or indolyl;
Consisting of a compound of formula (I), wherein any one or more or all of

A third group of interesting compounds (referred to herein as group “G3”) has the following restrictions: a) m is 0 or 2;
b) n is 0, 2 or 3;
c) p is 1;
d) s is 1;
e) t is 1,
f) X is C (= O);
g)

Is —C (═O) —CH <, —C (═O) —N <, —CHR ⁹ —CH <or —CHR ⁹ —N <;
h) R ¹ is aryl; heteroaryl; C _1-6 alkyloxycarbonyl; C _1-12 alkyl; or hydroxy, aryl, heteroaryl, amino, C _1-6 alkyloxy, mono or di (C _{1- 6} alkyl) amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C _1-6 alkylpiperazinyl, aryl C _1-6 alkylpiperazinyl, heteroaryl C _1-6 alkylpiperazinyl, C _3-7 cycloalkylpipe C _1-12 alkyl substituted with 1 or 2 substituents independently selected from radinyl and C _3-7 cycloalkylC _1-6 alkylpiperazinyl;
i) ^{R 3} _{is, C 1-6 alkyl; C 3-7} cycloalkyl; hydroxy, amino, _{C 1-6} alkyl substituted with a substituent selected from aryl and heteroaryl; or hydroxy, amino, aryl And C _3-7 cycloalkyl substituted with a substituent selected from heteroaryl;
j) R ⁴ and R ⁵ are each independently C _1-6 alkyl, polyhaloC _1-6 alkyl, hydroxy C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxyl, amino or C _2-6 Alkenyl; especially C _1-6 alkyl, polyhalo C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy or amino;
k) R ⁴ and R ⁵ together form a divalent group selected from methylenedioxy or ethylenedioxy;
l) R ⁶ is C _1-6 alkyloxycarbonyl or C _1-6 alkyl;
m) R ⁷ is hydrogen, aryl C _1-6 alkyl, hydroxy or heteroaryl C _1-6 alkyl; and n) Z is (a-1), (a-3), (a-4), ( a-5), (a-6), (a-7) and (a-8).
Consisting of a compound of formula (I), wherein any one or more or all of

A fourth group of interesting compounds (referred to herein as group “G4”) has the following restrictions: a) X is C (═O) or CHR ⁸ , preferably CHR ⁸ , where R ⁸ is hydrogen, —C (═O) —NR ¹⁷ R ¹⁸ , aryl C _1-6 alkyloxycarbonyl, C _1-6 alkyl substituted with hydroxy, piperazinylcarbonyl substituted with hydroxy, Hydroxy C _1-6 alkyl, hydroxy C _1-6 alkyloxy C _1-6 alkyl, pyrrolidinyl substituted with hydroxy C _1-6 alkyl, or hydroxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy _{C 1-6 alkyl, C 1-6} alkyl _{(dihydroxy) C 1-6} alkyl or _{C 1-6} alkyloxy (hydrate Carboxymethyl) be a C _1-6 piperidinylcarbonyl substituted with 1 or 2 substituents selected from alkyl;
b) R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, di (C _1-6 alkyl) amino C _1-6 alkyl, aryl C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl And hydroxy C _1-6 alkyl each independently selected;
c)

Is —CR ⁹ ═C <, —CHR ⁹ —CH <or —CHR ⁹ —N <;
d) ^{R 1} is hydrogen, _{heteroaryl, C 1-6 alkyloxycarbonyl, C 1-12} alkyl, or be a _{C 1-12} alkyl substituted with heteroaryl;
e) R ³ is hydrogen, C _1-6 alkyl or heteroaryl;
f) R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxy C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxyl, C _2-6 alkenyl or C _{1- 6} alkyloxy; especially hydrogen, halo, C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy or C _1-6 alkyloxy;
g) when p is 1, R ⁷ is aryl C _1-6 alkyl or hydroxy; h) Z is (a-1), (a-2), (a-3), (a-4) ), (A-5), (a-7), (a-8) and (a-9);
i) R ¹⁰ or R ¹¹ is hydrogen, halo, hydroxy, amino, C _1-6 alkyl, nitro, polyhaloC _1-6 alkyl, cyano, cyano C _1-6 alkyl, tetrazolo C _1-6 alkyl, aryl, Heteroaryl, heteroaryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, arylcarbonyl, C _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl (hydroxy) C _{1 -6} alkyl, aryl C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkylcarbonyloxy C _1-6 alkyl, C _{1 -6} alkyloxycarbonyl _{C 1-6} alkyloxy _{C 1-6} alkyl, hydroxy C _-6 alkyloxy _{C 1-6-alkyl, C 1-6} alkyloxycarbonyl _{C 2-6 alkenyl, C 1-6} alkyloxy _{C 1-6 alkyl, C 1-6} alkyloxycarbonyl, aminocarbonyl, hydroxy _{C 1- 6} alkyl, amino C _1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C _1-6 alkyl and — (CH ₂ ) _v — (C (═O)) _r — (CHR ¹⁹ ) _u —NR ¹³ R ¹⁴ each independently Is selected;
j) v is 0 or 1;
k) u is 0 or 1;
l) R ¹² is hydrogen or C _1-6 alkyl;
m) R ¹³ and R ¹⁴ are hydrogen; C _1-12 alkyl; C _1-6 alkylcarbonyl; C _1-6 alkylsulfonyl; aryl C _1-6 alkylcarbonyl; C _3-7 cycloalkylcarbonyl; ₂ ) _k— NR ¹⁵ R ¹⁶ ; C _1-12 alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl or aryl;
n) R ¹³ and R ¹⁴ together with the nitrogen to which they are attached, are morpholinyl, pyrrolidinyl, piperazinyl, or a substituent selected from C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl Forming a substituted piperazinyl;
o) k is 2;
p) R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, C _1-12 alkyl or aryl C _1-6 alkyloxycarbonyl; especially hydrogen, C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl;
q) R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form piperazinyl substituted with morpholinyl, piperazinyl, or C _1-6 alkyloxycarbonyl;
r) aryl is phenyl or phenyl substituted with halo;
s) heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and t) each pyridinyl, indolyl, oxadiazolyl or tetrazolyl is optionally selected from C _1-6 alkyl, aryl or arylC _1-6 alkyl Can be substituted with one substituent.
Consisting of a compound of formula (I), wherein any one or more or all of

A fifth group of interesting compounds (referred to herein as group “G5”) has the following restrictions: a) m is 0;
b) n is 1 or 2;
c) p is 0;
d) s is 0;
e) t is 0;
f) X is CHR ⁸ ;
g) R ⁸ is hydrogen;
h)

There is ^-CR 9 = C <;
i) R ⁹ is hydrogen or C _1-6 alkyl;
j) R ¹ is hydrogen;
k) R ³ is hydrogen;
l) R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl or C _1-6 alkyloxy;
m) R ⁶ is hydrogen;
n) Z is a group selected from (a-1), (a-2) and (a-4);
o) R ¹⁰ and R ¹¹ are each independently selected from hydrogen, hydroxy or hydroxy C _1-6 alkyl;
p) R ² and R ²⁰ are halo, cyano, polyhaloC _1-6 alkyl, C _1-6 alkyl, morpholinyl, C _1-6 alkyloxy, hydroxy C _1-6 alkyl, —NR ²¹ R ²² [where Each independently selected from: R ²¹ is hydrogen and R ²² is C _1-6 alkylcarbonyl; or R ² and R ²⁰ together with the phenyl ring to which they are attached are naphthalenyl Or one of R ² or R ²⁰ is as defined above and the other of R ² or R ²⁰ together with R ⁹ forms a direct bond,
Consisting of a compound of formula (I), wherein any one or more or all of

A sixth group of interesting compounds (referred to herein as group “G6”) is
X is C (═O) or CHR ⁸ , preferably CHR ⁸ , and R ⁸ is hydrogen; —C (═O) —NR ¹⁷ R ¹⁸ ; aryl C _1-6 alkylcarbonyl; substituted with hydroxyl C _1-6 alkyl; piperazinylcarbonyl substituted with hydroxyl; hydroxy C _1-6 alkyl; hydroxy C _1-6 alkyloxy C _1-6 alkyl; substituted with hydroxy C _1-6 alkyl Pyrrolidinyl; or hydroxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyl (dihydroxy) C _1-6 alkyl or C _1-6 alkyl Piperidinyl substituted with one or two substituents selected from oxy (hydroxy) C _1-6 alkyl Is carbonyl;
R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, di (C _1-6 alkyl) amino C _1-6 alkyl, aryl C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl or hydroxy Each independently selected from C _1-6 alkyl;

Is —CR ⁹ ═C <, —CHR ⁹ —CH <or —CHR ⁹ —N <;
R ¹ is hydrogen, _{heteroaryl, C 1-6 alkyloxycarbonyl, C 1-12} alkyl, or be a _{C 1-12} alkyl substituted with heteroaryl;
R ³ is hydrogen, C _1-6 alkyl or heteroaryl;
R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxy C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxyl, C _2-6 alkenyl or C _1-6 alkyl Oxy; especially hydrogen, halo, C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy or C _1-6 alkyloxy;
when p is 1, R ⁷ is arylC _1-6 alkyl or hydroxy;
Z is from (a-1), (a-2), (a-3), (a-4), (a-5), (a-7), (a-8) and (a-9). A selected group;
R ¹⁰ or R ¹¹ is hydrogen; halo; hydroxyl; amino; C _1-6 alkyl; nitro; polyhaloC _1-6 alkyl; cyano; cyano C _1-6 alkyl; tetrazolo C _1-6 alkyl; Heteroaryl C _1-6 alkyl; aryl (hydroxy) C _1-6 alkyl; arylcarbonyl; C _1-6 alkylcarbonyl; C _3-7 cycloalkylcarbonyl; C _3-7 cycloalkyl (hydroxy) C _1-6 Alkyl; aryl C _1-6 alkyloxy C _1-6 alkyl; C _1-6 alkyloxy C _1-6 alkyloxy C _1-6 alkyl; C _1-6 alkylcarbonyloxy C _1-6 alkyl; C _1-6 alkyloxycarbonyl _{C 1-6} alkyloxy _{C 1-6} alkyl; hydroxy _{C 1 6} alkyloxy _{C 1-6 alkyl; C 1-6} alkyloxycarbonyl _{C 2-6 alkenyl; C 1-6} alkyloxy _{C 1-6 alkyl; C 1-6} alkyloxycarbonyl; aminocarbonyl; hydroxy _{C 1-6} Alkyl; amino C _1-6 alkyl; hydroxycarbonyl; hydroxycarbonyl C _1-6 alkyl and — (CH ₂ ) _v — (C (═O)) _r — (CHR ¹⁹ ) _u —NR ¹³ R ¹⁴ each independently Selected; v is 0 or 1;
u is 0 or 1;
R ¹² is hydrogen or C _1-6 alkyl;
R ¹³ and R ¹⁴ are hydrogen; C _1-12 alkyl; C _1-6 alkylcarbonyl; C _1-6 alkylsulfonyl; aryl C _1-6 alkylcarbonyl; C _3-7 cycloalkylcarbonyl; — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ ; each independently selected from C _1-12 alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl or aryl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached are substituted with morpholinyl, pyrrolidinyl, piperazinyl, or a substituent selected from C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl Forming piperazinyl;
k is 2;
Whether R ¹⁵ and R ¹⁶ are independently selected from hydrogen, C _1-12 alkyl or aryl C _1-6 alkyloxycarbonyl; especially hydrogen, C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl; Or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form morpholinyl; piperazinyl; or piperazinyl substituted with C _1-6 alkyloxycarbonyl;
Aryl is phenyl or phenyl substituted with halo; and heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl or tetrazolyl is optionally C _1- Can be substituted with one substituent selected from ₆ alkyl, aryl or aryl C _1-6 alkyl,
It consists of a compound of formula (I) or any subgroup thereof.

A seventh group of more preferred compounds (referred to herein as group “G7”) is:
m is 0; n is 1 or 2, especially 1, p is 0; s is 0; t is 0; X is CH ₂ ;

Is —CR ⁹ ═C <and R ⁹ is hydrogen or C _1-6 alkyl, preferably hydrogen or methyl, more preferably hydrogen, or R ⁹ together with one of R ² or R ²⁰ To form a direct bond; R ¹ is hydrogen; R ³ is hydrogen; and R ⁶ is hydrogen;
It consists of a compound of formula (I).

An eighth group of more preferred compounds (referred to herein as group “G8”) is
R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxy C _1-6 alkyl, polyhalo C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy, amino, C _{2 -6} alkenyl or C _1-6 alkyloxy; especially hydrogen, halo, C _1-6 alkyl, polyhalo C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy, amino or C _1-6 alkyloxy Yes;
More preferably, R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxyl C _1-6 alkyl, polyhalo C _1-6 alkyl, hydroxy, amino C _2-6 alkenyl or C _{1 -6} alkyloxy; especially hydrogen, halo, C _1-6 alkyl, polyhalo C _1-6 alkyl, hydroxy, amino or C _1-6 alkyloxy;
Even more preferably, R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxyl C _1-6 alkyl, hydroxyl, C _2-6 alkenyl or C _1-6 alkyloxy; especially hydrogen , Halo, C _1-6 alkyl, hydroxy or C _1-6 alkyloxy;
Most preferably, R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl or C _1-6 alkyloxy (eg, R ⁴ and R ⁵ may be each independently hydrogen, methyl or methyloxy)
It consists of a compound of formula (I) as defined above or a compound of group "G7".

A ninth group of more preferred compounds (referred to herein as group “G9”) is
Whether Z is a group selected from (a-1), (a-2), (a-3), (a-4) and (a-5);
Or, preferably Z is a group selected from (a-1), (a-2) and (a-4).
It consists of a compound of formula (I) as defined above, or a compound of either group “G7” or “G8”.

A tenth group of more preferred compounds (referred to herein as group “G10”) is:
R ¹⁰ or R ¹¹ is hydrogen, halo, hydroxy, amino, C _1-6 alkyl, nitro, polyhalo C _1-6 alkyl, cyano, cyano C _1-6 alkyl, tetrazolo C _1-6 alkyl, aryl, heteroaryl , Heteroaryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, arylcarbonyl, C _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl (hydroxy) C _1-6 Alkyl, aryl C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkylcarbonyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl _{C 1-6} alkyloxy _{C 1-6} alkyl, hydroxy _{C 1-} Alkyloxy _{C 1-6 alkyl, C 1-6} alkyloxycarbonyl _{C 2-6 alkenyl, C 1-6} alkyloxy _{C 1-6 alkyl, C 1-6} alkyloxycarbonyl, aminocarbonyl, hydroxy _{C 1-6} alkyl , Amino C _1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C _1-6 alkyl and — (CH ₂ ) _v — (C (═O)) _r — (CHR ¹⁹ ) _u —NR ¹³ R ¹⁴ each independently selected Is;
v is 0 or 1;
r is 0 or 1;
u is 0 or 1;
R ¹³ and R ¹⁴ are hydrogen; C _1-12 alkyl; C _1-6 alkylcarbonyl; C _1-6 alkylsulfonyl; aryl C _1-6 alkylcarbonyl; C _3-7 cycloalkylcarbonyl; — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ ; each independently selected from C _1-12 alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl or aryl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached are substituted with morpholinyl, pyrrolidinyl, piperazinyl, or a substituent selected from C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl Forming piperazinyl;
k is 2;
Whether R ¹⁵ and R ¹⁶ are independently selected from hydrogen, C _1-12 alkyl or aryl C _1-6 alkyloxycarbonyl; especially hydrogen, C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl; Or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form piperazinyl substituted with morpholinyl, piperazinyl, or C _1-6 alkyloxycarbonyl;
R ¹² is hydrogen or C _1-6 alkyl,
It consists of a compound of formula (I) as defined above or a compound of any of the group "G7", "G8" or "G9".

An eleventh group of more preferred compounds (referred to herein as group “G11”) is:
R ¹⁰ or R ¹¹ is hydrogen, hydroxy, amino, C _1-6 alkyl, nitro, polyhaloC _1-6 alkyl, cyano, aryl, aryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, aryl Carbonyl, C _1-6 alkyloxy, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, hydroxycarbonyl and — (CH ₂ ) _v — (C (═O)) _r — (CH ₂ ) _u —NR ¹³ R ¹⁴ each independently selected;
v is 0 or 1;
r is 0 or 1;
u is 0;
R ¹³ and R ¹⁴ are each independently selected from hydrogen, C _1-6 alkyl, — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ , and C _1-12 alkyl substituted with hydroxy; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form pyrrolidinyl;
k is 2;
R ¹⁵ and R ¹⁶ are each independently C _1-6 alkyl;
R ¹² is hydrogen or C _1-6 alkyl, preferably hydrogen,
It consists of the compounds of group “G10” as defined above.

A twelfth group of more preferred compounds (referred to herein as group “G12”) is:
R ¹⁰ and R ¹¹ are each independently selected from hydrogen, hydroxy and hydroxy C _1-6 alkyl; and R ¹² is hydrogen or C _1-6 alkyl, preferably hydrogen (eg, R ¹⁰ and R ¹¹ Each can be independently selected from hydrogen, hydroxy and hydroxymethyl; and R ¹² can be hydrogen or methyl, preferably hydrogen),
It consists of the compounds of group “G10” as defined above.

A thirteenth group of more preferred compounds (referred to herein as group “G13”) is
Aryl is phenyl, or phenyl substituted with halo; and heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl or tetrazolyl is optionally C _1-6 Can be substituted with one substituent selected from alkyl, aryl and arylC _1-6 alkyl;
Compounds of formula (I) as defined above or the groups “G7”, “G8”, “G9”, “G
10 ”,“ G11 ”or“ G12 ”.

A fourteenth group of more preferred compounds (referred to herein as group “G14”) is
Aryl is phenyl or phenyl substituted with halo; and heteroaryl is pyridinyl or indolyl;
It consists of the compounds of group “G13” as defined above.

A fifteenth group of particularly preferred compounds (referred to herein as group “G15”) is
m is 0; n is 1 or 2, especially 1, p is 0; s is 0; t is 0; X is CH ₂ ;

Is —CR ⁹ ═C <and R ⁹ is hydrogen or C _1-6 alkyl, more preferably hydrogen, or R ⁹ is directly bonded together with one of R ² or R ²⁰ R ¹ is hydrogen; R ³ is hydrogen; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl or C _1-6 alkyloxy; especially hydrogen, C _1-6 alkyl or C _1-6 alkyloxy; R ⁶ is hydrogen; Z is (a-1), (a-2) and (a-4) And R ¹⁰ or R ¹¹ are each independently hydrogen, hydroxy or hydroxy C _1-6 alkyl,
It consists of a compound of formula (I) or any subgroup thereof.

A sixteenth group of particularly preferred compounds (referred to herein as group “G16”) is
m is 0; n is 1 or 2, especially 1, p is 0; s is 0; t is 0; X is CH ₂ ;

There is ^-CR 9 = C <, and, if ^{R 9} is hydrogen or methyl, or, ^{R 9} form a direct bond together with one of ^{R 2} or ^{R 20; R 1} is hydrogen R ³ is hydrogen; R ⁴ and R ⁵ are each independently hydrogen, methyl or methyloxy; R ⁶ is hydrogen; Z is (a-1), (a-2) and (a -4); and R ¹⁰ or R ¹¹ are each independently hydrogen, hydroxy or hydroxymethyl,
It consists of a compound of formula (I) or any subgroup thereof.

  A seventeenth group of particularly preferred compounds (referred to herein as group “G17”) is:

Is —CR ⁹ ═C <(and then the dotted line is a bond), —C (═O) —CH <, —CHR ⁹ —CH <or —CHR ⁹ —N <, wherein each R ⁹ is independently Hydrogen or C _1-6 alkyl, or R ⁹ together with one of R ² or R ²⁰ forms a direct bond;

Is —CR ⁹ ═C <(and then the dotted line is a bond), —CHR ⁹ —CH <or —CHR ⁹ —N <, wherein each R ⁹ is independently hydrogen or C _1-6 alkyl Or R ⁹ together with one of R ² or R ²⁰ forms a direct bond;

Is —CR ⁹ = C <, and then the dotted line is a bond, each R ⁹ is independently hydrogen or C _1-6 alkyl, or R ⁹ is together with one of R ² or R ²⁰ Become a direct bond,
It consists of a compound of formula (I) as defined above, or any subgroup thereof whenever possible.

Preferably, in the compounds of formula (I), and especially in any one of the groups “G1” to “G17” above, the substituents on the central phenyl ring other than R ² and R ²⁰ are para (p It can be in the-) position.

In one embodiment, when m is 1, when substituents on the phenyl ring other than R ² and R ²⁰ are in the meta position, when s is 0 and t is 0; Z is a group selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7) or (a-8). sell.

In a preferred embodiment, the compound of formula (I) and especially any one of the groups “G1” to “G17” above (any of “groups“ G1 ”to“ G17 ”as used throughout this specification). The enumeration “one” refers to the compound groups “G1”, “G2”, “G3”, “G4”, “G5”, “G6”, “G7”, “G8”, as defined herein. Includes specific reference to any one or each of “G9”, “G10”, “G11”, “G12”, “G13”, “G14”, “G15”, “G16” or “G17” R ² and R ²⁰ are halo, cyano, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, aryl, heteroaryl, arylC _1-6 alkyl, hetero aryl _{C 1-} Alkyl, hydroxy _{C 1-6} alkyl, polyhaloC _{C 1-6} alkyl preferably perhalo _{C 1-6 alkyl, C 1-6} alkyloxy, polyhaloC _{C 1-6} alkyloxy preferably perhalo _{C 1-6} alkyloxy, aryl C _1-6 alkyloxy, heteroaryl C _1-6 alkyloxy, C _1-6 alkylthio, arylthio preferably phenylthio, C _1-6 alkylcarbonyl, hydroxy C _1-6 alkylcarbonyl, C _1-6 alkyloxycarbonyl, C _{1-6 alkylcarbonyloxy, C 1-6} alkylcarbonylamino, morpholinyl, piperidinyl, or are each independently selected from pyrrolidinyl and piperazinyl; or, ^{R 2} and ^{R 20,} a naphthalenyl together with the central phenyl ring Formation That.

In another preferred embodiment, in the compound of formula (I), and especially any one compound of the above groups “G1” to “G17”, R ² and R ²⁰ are C _1-6 alkyl, aryl, Heteroaryl, arylC _1-6 alkyl, heteroaryl C _1-6 alkyl,
Hydroxy C _1-6 alkyl, polyhalo C _1-6 alkyl, polyhalo C _1-6 alkyloxy, C _1-6 alkyloxy, aryl C _1-6 alkyloxy, heteroaryl C _1-6 alkyloxy, C _{1-6 Alkylthio} , arylthio preferably phenylthio, C _1-6 alkylcarbonyl, hydroxy C _1-6 alkylcarbonyl, C _1-6 alkyloxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonylamino, morpholinyl, piperidinyl, Each independently selected from pyrrolidinyl and piperazinyl, any of the foregoing groups being halo, hydroxy, cyano, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, aryl , Heteroaryl One or more selected from fine C _1-6 alkyloxy, or preferably substituted in the and independently with 1 or 2 substituents; or, R ² and R ²⁰ and the central phenyl ring Together they form naphthalenyl.

In one particularly preferred embodiment, in the compound of formula (I) and especially any one compound of the above groups “G1” to “G17”, R ² and R ²⁰ are halo, cyano, C _1-6 Each independently selected from alkyl, hydroxy C _1-6 alkyl, polyhalo C _1-6 alkyl, preferably perhalo C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylcarbonylamino and morpholinyl; or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl.

In another preferred embodiment, in the compound of formula (I), and especially any one compound of the above groups “G1” to “G17”, R ² and R ²⁰ are halo, C _1-6 alkyl, Polyhalo C _1-6 alkyl, preferably each independently selected from perhalo C _1-6 alkyl and C _1-6 alkyloxy, or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl.

In another preferred embodiment, in the compounds of formula (I), and especially any one of the above groups “G1” to “G17”, R ² and R ²⁰ are halo, C _1-6 alkyl and C Each is independently selected from _1-6 alkyloxy.

In another preferred embodiment, in the compound of formula (I) and any one of the groups “G1” to “G17” above, R ² and R ²⁰ are halo, C _1-6 alkyl, C _1- Each is independently selected from ₆ alkyloxy, hydroxy C _1-6 alkyl, or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl.

In another particularly preferred embodiment, in the compound of formula (I), and especially any one of the groups “G1” to “G17” above, R ² and R ²⁰ are fluoro, chloro, bromo, cyano , Methyl, hydroxymethyl, trihalomethyl, preferably trifluoromethyl, methyloxy, methylcarbonylamino and morpholinyl each independently or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl .

In a further preferred embodiment, in the compound of formula (I), and especially any one of the groups “G1” to “G17” above, R ² and R ²⁰ are fluoro, chloro, methyl, trifluoromethyl. And methyloxy each independently or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl.

In a further preferred embodiment, in the compound of formula (I), and especially any one compound of the above groups “G1” to “G17”, R ² and R ²⁰ are from fluoro, chloro, methyl and methyloxy. Each is selected independently.

In another preferred embodiment, in the compound of formula (I) and any one of the groups “G1” to “G17” above, R ² and R ²⁰ are fluoro, chloro, bromo, methyl, methyl Each independently selected from oxy, hydroxymethyl, or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl.

In another preferred embodiment, in the compounds of formula (I) and especially any one of the groups “G1” to “G17” above, R ² and R ²⁰ are halo, cyano, polyhaloC _{1- 6} alkyl, C _1-6 alkyl, morpholinyl, C _1-6 alkyloxy, hydroxyl C _1-6 alkyl, —NR ²¹ R ²² [where R ²¹ is hydrogen and R ²² is C _1-6 alkylcarbonyl Each of R ² and R ²⁰ together with the phenyl ring to which they are attached form a naphthalenyl, or one of R ² or R ²⁰ is And the other of R ² or R ²⁰ together with R ⁹ form a direct bond; in particular, R ² and R ²⁰ are chloro , Fluoro, bromo, cyano, trifluoromethyl, methyl, morpholinyl, methyloxy, hydroxymethyl, —NH—C (═O) —CH ₃ each independently; or R ² and R ²⁰ are Together with the phenyl ring to which they are attached form a naphthalenyl group, or one of R ² or R ²⁰ is as defined above and the other of R ² or R ²⁰ Together with R ⁹ form a direct bond.

Some preferred but non-limiting embodiments of compounds of formula (I), in particular any one of the groups “G1” to “G17” above, show combinations of R ² and R ²⁰ substituents shown in Table 1. Including compounds that are as defined above.

In one aspect, particularly interesting combinations of R ² and R ²⁰ are combinations numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 17 as defined in Table 1. Specifically, combination numbers 2, 4, 6, 8, 9, 11, and 17 as defined in Table 1 are included.

In another aspect, particularly interesting combinations of R ² and R ²⁰ are defined as combination numbers 5, 6, 7, 8, 9, 10 and 11 as defined in Table 1, and more specifically as defined in Table 1. The combination numbers 10 and 11 are included.

In a further aspect, particularly interesting combinations of R ² and R ²⁰ are combination numbers 1, 2, 5, 6, 7, 8, 9, 10, 11, 14, 15 and 17, as defined in Table 1. More specifically, combination numbers 10 and 11 as defined in Table 1 are included.

Thus, an exemplary preferred group of compounds is
m is 0; n is 1 or 2; p is 0; s is 0; t is 0; X is CH ₂ ;

Is —CR ⁹ ═C <, and R ⁹ is hydrogen or C _1-6 alkyl, more preferably hydrogen; R ¹ is hydrogen; R ³ is hydrogen; R ⁴ and R ⁵ are each Independently hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl or C _1-6 alkyloxy; R ⁶ is hydrogen; Z is (a-1), (a- 2) and (a-4); R ¹⁰ or R ¹¹ is each independently hydrogen, hydroxy or hydroxy C _1-6 alkyl; R ¹² is hydrogen or C _1-6 alkyl, preferably It is hydrogen; and ^{R 2} and ^{R 20} is halo, _{cyano, C 1-6} alkyl, hydroxy _{C 1-6} alkyl, polyhaloC _{C 1-6} alkyl preferably perhalo _{C 1-6} alkyl C _{1-6 alkyloxy,} or are each independently selected from _{C 1-6} alkylcarbonylamino and morpholinyl, or ^{R 2} and ^{R 20} form a naphthalenyl together with the central phenyl ring; or, R ^{One of 2} or R ²⁰ is as defined above and the other of R ² or R ²⁰ together with R ⁹ forms a direct bond;
More preferably, R ² and R ²⁰ are each independently selected from halo, C _1-6 alkyl, polyhalo C _1-6 alkyl, preferably perhalo C _1-6 alkyl and C _1-6 alkyloxy, or , R ² and R ²⁰ together with the central phenyl ring form naphthalenyl;
Even more preferably, R ² and R ²⁰ can each be independently selected from halo, C _1-6 alkyl and C _1-6 alkyloxy;
Also more preferably, R ² and R ²⁰ can each be independently selected from halo, C _1-6 alkyl, C _1-6 alkyloxy, hydroxy C _1-6 alkyl, or R ² and R ²⁰ together with the central phenyl ring forms naphthalenyl;
Even more preferably, R ² and R ²⁰ are each independently selected from fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trihalomethyl, preferably trifluoromethyl, methyloxy, methylcarbonylamino and morpholinyl; Or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl; or one of R ² or R ²⁰ is as defined above and the other of R ² or R ²⁰ Together with R ⁹ form a direct bond;
Even more preferably, R ² and R ²⁰ are each independently selected from fluoro, chloro, methyl, trifluoromethyl and methyloxy, or R ² and R ²⁰ together with the central phenyl ring form naphthalenyl. Forming;
Even more preferably, R ² and R ²⁰ are each independently selected from fluoro, chloro, methyl and methyloxy;
More preferably, R ² and R ²⁰ are each independently selected from fluoro, chloro, bromo, methyl, methyloxy, hydroxymethyl, or R ² and R ²⁰ together with the central phenyl ring are naphthalenyl Forming;
And particularly preferably, R ² and R ²⁰ may be as shown in Table 1,
It consists of a compound of formula (I) or any subgroup thereof.

  Another embodiment is a compound of formula (I)

A compound of
Consisting of their N-oxide forms, addition salts, solvates or stereoisomers,
Where m is 0, 1 or 2, and when m is 0, a direct bond is intended;
n is 0, 1, 2 or 3, and when n is 0, a direct bond is intended;
p is 0 or 1, and when p is 0, a direct bond is intended;
s is 0 or 1, and when s is 0, a direct bond is intended;
t is 0 or 1, and when t is 0, a direct bond is intended;
X is C (═O) or CHR ⁸ , where R ⁸ is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, —C (═O) —NR ¹⁷ R ¹⁸ , carboxyl, aryl C _1-6 alkyloxycarbonyl, heteroaryl, heteroarylcarbonyl, heteroaryl C _1-6 alkyloxycarbonyl, piperazinylcarbonyl, pyrrolidinyl, piperidinylcarbonyl, C _1-6 alkyloxycarbonyl, hydroxy, amino, aryl and C _1-6 alkyl substituted with a substituent selected from heteroaryl, C _3-7 cycloalkyl, hydroxy, hydroxy C ₁ substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl _-6 alkyl and hydroxy _{C 1-6} Arukiruoki C _1-6 piperazinylcarbonyl substituted with a substituent selected from alkyl, pyrrolidinyl substituted by hydroxy _{C 1-6} alkyl, and, _{hydroxy, C 1-6} alkyl, hydroxy _{C 1-6} alkyl 1 or 2 substituents selected from C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyl (dihydroxy) C _1-6 alkyl and C _1-6 alkyloxy (hydroxy) C _1-6 alkyl Selected from piperidinylcarbonyl substituted with
R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, di (C _1-6 alkyl) amino C _1-6 alkyl, aryl C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl, hydroxy Each independently selected from C _1-6 alkyl, hydroxy C _1-6 alkyl (C _1-6 alkyl) or hydroxy C _1-6 alkyl (aryl C _1-6 alkyl);

Is —CR ⁹ ═C <(and the dotted line is a bond), —C (═O) —CH <, —C (═O) —N <, —CHR ⁹ —CH <or —CHR ⁹ —. N <and each R ⁹ is independently hydrogen or C _1-6 alkyl, or R ⁹ together with one of R ² or R ²⁰ forms a direct bond;
R ¹ is hydrogen; aryl, heteroaryl, C _1-6 alkyloxycarbonyl, C _1-12 alkyl, or hydroxy, aryl, heteroaryl, amino, C _1-6 alkyloxy, mono or di (C _1-6 Alkyl) amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C _1-6 alkylpiperazinyl, aryl C _1-6 alkylpiperazinyl, heteroaryl C _1-6 alkylpiperazinyl, C _3-7 cycloalkylpiperazinyl And C _1-12 alkyl substituted with 1 or 2 substituents independently selected from C _3-7 cycloalkylC _1-6 alkylpiperazinyl;
R ² and R ²⁰ are
Halo, hydroxy, cyano, nitro, carboxyl;
Polyhalo C _1-6 alkyl, perhalo C _1-6 alkyl, polyhalo C _1-6 alkyloxy, perhalo C _1-6 alkyloxy;
C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl, aryl, heteroaryl, aryl C _1-6 alkyl, heteroaryl C _1-6 alkyl, C _3-7 cycloalkyl C _1-6 alkyl , Morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C _1-6 alkyloxy, aryloxy, heteroaryloxy, C _1-6 alkylthio, arylthio, heteroarylthio, C _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, arylcarbonyl, _{heteroarylcarbonyl, C 1-6 alkyloxycarbonyl, C 3-7} cycloalkyloxycarbonyl, aryloxycarbonyl, _{heteroaryloxycarbonyl, C 1-6 alkylcarbonyloxy, C 3-7} cycloalkyl Ruboniruokishi, both arylcarbonyloxy or heteroarylcarbonyloxy (of the group, halo, hydroxy, cyano, nitro, carboxyl, amino, mono- or di _{(C 1-6} alkyl) _{amino, C 1-6} alkyl, polyhalo C One or more selected from _1-6 alkyl, aryl, heteroaryl, C _1-6 alkyloxy, C _1-6 alkylcarbonyl, C _1-6 alkyloxycarbonyl and C _1-6 alkylcarbonyloxy, preferably Are optionally substituted independently with 1 or 2 substituents); and — (CH ₂ ) _w — (C (═O)) _y NR ²¹ R ^22, where w is 0, 1, 2, Direct binding is intended when 3, 4, 5 or 6 and w is 0;
if y is 0 or 1, and if y is 0, a direct bond is intended;
R ²¹ and R ²² are hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkylcarbonyl and aryl C _1-6 alkylcarbonyl (all of the above groups are halo, hydroxy, amino, mono Or one or more selected from di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyloxy, aryl and heteroaryl, preferably 1 or 2 Each independently selected from, optionally substituted with one substituent);
Or, R ²¹ and R ²² together with the nitrogen to which they are attached form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, any of the above groups being C _1-6 alkyl, polyhalo C _1-6 One or more selected from alkyl, C _1-6 alkyloxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, aryl C _1-6 alkyl and heteroaryl C _1-6 alkyl Above, preferably 1
Or optionally substituted independently by two substituents]
Are selected independently from each other;
Alternatively, R ² and R ²⁰ together with the phenyl ring to which they are attached, are halo, hydroxy, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhalo C ₁ Forms a naphthalenyl group optionally substituted with one or more, preferably 1 or 2 substituents selected from _-6 alkyl, C _1-6 alkyloxy, aryl and heteroaryl;
Alternatively, R ² and R ^{20 taken} together are halo, hydroxy, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyl. A formula — (CH ₂ ) _b — [where b is 3, 4 or optionally substituted with one or more, preferably 1 or 2, substituents selected from oxy, aryl and heteroaryl A divalent group of 5];
Alternatively, one of R ² or R ²⁰ is as defined above and the other of R ² or R ²⁰ together with R ⁹ forms a direct bond;
R ³ is _{hydrogen, C 1-6} alkyl, _{heteroaryl, C 3-7} cycloalkyl, hydroxy, amino, aryl and _{C 1-6} alkyl substituted with a substituent selected from heteroaryl, or hydroxy, C _3-7 cycloalkyl substituted with a substituent selected from amino, aryl and heteroaryl;
Are R ⁴ and R ⁵ each independently hydrogen, halo, C _1-6 alkyl, polyhaloC _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy, amino or C _1-6 alkyloxy? Or R ⁴ and R ⁵ together form a divalent group selected from methylenedioxy or ethylenedioxy;
R ⁶ is hydrogen, C _1-6 alkyloxycarbonyl or C _1-6 alkyl;
when p is 1, R ⁷ is hydrogen, arylC _1-6 alkyl, hydroxy or heteroarylC _1-6 alkyl;
Z is

Wherein R ¹⁰ or R ¹¹ is hydrogen, halo, hydroxy, amino, C _1-6 alkyl, nitro, polyhaloC _1-6 alkyl, cyano, cyano C _1-6 alkyl, tetrazolo C _1-6 alkyl, aryl, heteroaryl, aryl C _1-6 alkyl, heteroaryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, heteroaryl (hydroxy)
C _1-6 alkyl, arylcarbonyl, heteroarylcarbonyl, C _1-6 alkylcarbonyl, aryl C _1-6 alkylcarbonyl, heteroaryl C _1-6 alkylcarbonyl, C _1-6 alkyloxy, C _3-7 cycloalkyl Carbonyl, C _3-7 cycloalkyl (hydroxy) C _1-6 alkyl, aryl C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyloxy C _1-6 alkyl, C _{1 -6} alkylcarbonyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl C _1-6 alkyloxy C _1-6 alkyl, hydroxy C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl C _{2-6 alkenyl, C 1-6} alkyloxy _{C 1-6} Al _{Le, C 1-6 alkyloxycarbonyl, C 1-6} alkylcarbonyloxy, aminocarbonyl, hydroxy _{C 1-6} alkyl, amino _{C 1-6} alkyl, hydroxycarbonyl, hydroxycarbonyl _{C 1-6} alkyl and - (CH ₂ ) _V- (C (= O)) _r- (CHR ¹⁹ ) _u -NR ¹³ R ¹⁴
Where v is 0, 1, 2, 3, 4, 5 or 6 and when v is 0, a direct bond is intended;
r is 0 or 1, and when r is 0, a direct bond is intended;
u is 0, 1, 2, 3, 4, 5 or 6 and when u is 0, direct binding is intended;
R ¹⁹ is hydrogen or C _1-6 alkyl;
R ¹³ and R ¹⁴ are hydrogen, C _1-12 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, aryl C _1-6 alkylcarbonyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl Substituted with a substituent selected from carbonyl, — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ , hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl, C _1-6 alkyloxy, aryl or heteroaryl. Substituted with a substituent selected from C _1-12 alkyl, or hydroxy, C _1-6 alkyloxy, aryl, amino, aryl C _1-6 alkyl, heteroaryl or heteroaryl C _1-6 alkyl C _3-7 either each independently selected from cycloalkyl, is ^{R 13} and ^{R 14} together with the nitrogen to which they are attached, a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or _{C 1-6} alkyl, aryl _{C 1-6} alkyl, aryl _{C 1-6} alkyloxy Forming piperazinyl substituted with a substituent selected from carbonyl, heteroaryl C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 cycloalkyl C _1-6 alkyl; 1, 2, 3, 4, 5 or 6, and when k is 0, a direct bond is intended;
R ¹⁵ and R ¹⁶ are a substituent selected from hydrogen, C _1-12 alkyl, aryl C _1-6 alkyloxycarbonyl, C _3-7 cycloalkyl, hydroxy, C _1-6 alkyloxy, aryl and heteroaryl in _{C 1-12} alkyl substituted, and _{hydroxy, C 1-6} alkyloxy, aryl, aryl _{C 1-6} alkyl, substituted with a substituent selected from heteroaryl and heteroaryl _{C 1-6} alkyl Each independently selected from C _3-7 cycloalkyl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached, are morpholinyl, piperazinyl, or C _1-6 alkyloxycarbonyl Forming piperazinyl substituted with:
R ¹² is _{hydrogen, C 1-6 alkyl, C 3-7} cycloalkyl, hydroxy, _{amino, C 1-6} alkyloxy and _{C 1-6} alkyl substituted with a substituent selected from aryl, or a hydroxy C _3-7 cycloalkyl substituted with a substituent selected from amino, aryl and C _1-6 alkyloxy;
Aryl is phenyl or naphthalenyl;
Each phenyl or naphthalenyl is optionally 1, 2 or 3 substituents independently selected from halo, hydroxy, C _1-6 alkyl, amino, polyhalo C _1-6 alkyl and C _1-6 alkyloxy, respectively. And each phenyl or naphthalenyl can optionally be substituted with a divalent group selected from methylenedioxy and ethylenedioxy;
Heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;
Each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl may optionally be halo, hydroxy, C _1-6 alkyl, amino, polyhaloC _1-6 alkyl, aryl, aryl C Each may be substituted with 1, 2 or 3 substituents independently selected from _1-6 alkyl or C _1-6 alkyloxy; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl or The tetrahydrofuranyl can be optionally substituted with a divalent group selected from methylenedioxy or ethylenedioxy.

Especially Another aspect of the preferred compounds, s is be 0; t is be 0; m is be 0; p is located at 0; n is 1 or 2; R ¹ is hydrogen; R ² And R ²⁰ is halo, cyano, polyhaloC _1-6 alkyl, C _1-6 alkyl, morpholinyl, C _1-6 alkyloxy, hydroxy C _1-6 alkyl, —NR ²¹ R ²² [where R ²¹ is hydrogen And R ²² is C _1-6 alkylcarbonyl] each independently; or R ² and R ²⁰ together with the phenyl ring to which they are attached form a naphthalenyl group or is as one of ^{R 2} or ^{R 20} is defined above, and others of ^{R 2} or ^{R 20} forms a direct bond together with ^{R 9; R 3} is hydrogen Yes; R And ^{R 5} are each independently _{hydrogen, C 1-6 alkyl, C 1-6} alkyloxy, hydroxy _{C 1-6 alkyl, C 2-6} alkenyl; ^{R 6} is hydrogen;

Is —CR ⁹ ═C <, and the dotted line is a bond; R ⁹ is hydrogen or C _1-6 alkyl; X is CH ₂ ; Z is (a-1), (a− 2) or a group selected from (a-4); consisting of a compound of formula (I), wherein R ¹⁰ and R ¹¹ are each independently selected from hydrogen, hydroxy and hydroxy C _1-6 alkyl.

In compounds of formula (I), and in particular any one of the groups “G1” to “G17” above, R ² and R ²⁰ together with the phenyl ring to which they are attached, When forming an optionally substituted naphthalenyl group as defined above, the substituent

It should be appreciated that can be attached to either the same ring or different rings of the naphthalenyl group.

In one preferred embodiment, R ² and R ²⁰ are taken together with the phenyl ring to which they are attached to formulas (II-a) and (II-b), more preferably formula (II-a):

Wherein the substituent has the meaning as defined above,
Can form a naphthalenyl group that can be drawn by:

In another embodiment, in a compound of formula (I), and especially any one compound of groups “G1” to “G17” above, one of R ² or R ²⁰ is as defined above. And the other of R ² or R ²⁰ together with R ⁹ form a direct bond. As an example,

A compound of formula (I) in which —CR ⁹ ═C <and R ²⁰ together with R ⁹ form a direct bond is represented by the general formula (III):

The substituents here can be drawn to have the meanings as defined above.

Preferably, when one of R ² or R ²⁰ together with R ⁹ forms a direct bond, the direct bond is adjacent to the carbon of the central phenyl ring to which the — (CH ₂ ) _m — group is attached. It can be attached to the carbon of the central phenyl ring (ie o-position).

As can be appreciated, in the compounds of formula (I), and especially any one of the above groups "G1" to "G17", the substituents R ² and R ²⁰ are relative to each other on the central phenyl ring. It can be in the ortho (o-), meta (m-) or para (p-) position.

R ² and R ²⁰ together form a divalent group of the formula — (CH ₂ ) _b —, where b is 3, 4 or 5, optionally substituted as above. In some cases, the bond of the divalent group is preferably bonded in the ortho (o-) position with respect to each other of the central phenyl ring.

As can be appreciated, in the compounds of formula (I), and in particular any one of the groups “G1” to “G17” above, the four substituents on the central phenyl ring can be in various positions relative to each other. It is possible. For example, and without limitation, when the substituent on the central phenyl other than R ² and R ²⁰ is in the para position, ie 1-, 4-, the R ² and R ²⁰ substituents are in positions 2- and 3-, or It can be in positions 2- and 5-, or positions 2- and 6-, etc.

  Table 2 lists preferred but non-limiting examples of compounds of formula (I) prepared in the present invention. The following abbreviations were used in the table. That is,. HCl stands for hydrochloride, mp. Represents melting point.

In one embodiment, compound numbers 2, 5, 6, 10, 12, 17, 25, 29, 30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 and 49 are particularly preferred and compound numbers 5, 6, 10, 17, 29, 30, 31, 34, 35, 39, 40, 41, 42, 43, 44, 45, 46, 47 ,
48 and 49 are even more preferred, and compound numbers 5, 39, 41, 42, 43 and 47 are even more preferred; these compounds can achieve a particularly significant desired biological effect.

  In another embodiment, compound numbers 7, 9, 17, 29, 30, 31, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 49 are particularly preferred, and compound number 42 is even more Preferably; these compounds can achieve particularly desirable biological effects.

  In a further aspect, compound numbers 2, 6, 8, 10, 11, 12, 13, 15, 17, 18, 19, 22, 29, 30, 31, 32, 38, 39, 40, 41, 42, 43 44, 45, 46, 47, 48, 51, 52 and 53 are particularly preferred, and compound numbers 38, 39, 42, 44, 45, 46 and 47 are even more preferred; Achieving a scientific effect.

In a further embodiment, any stereoisomer thereof;
Particularly preferred are the following compounds, including their N-oxides, their acid addition salts or their solvates:

  In a further aspect, compound numbers 39, 41, 42, 47, 49 and 63 are particularly preferred.

  Compounds of formula (I), their N-oxides, pharmaceutically acceptable salts, solvates, and their stereoisomers may be prepared in a conventional manner. Some of the starting materials and intermediates are known compounds and are commercially available or can be prepared according to conventional reaction procedures known in the art.

  A number of such manufacturing methods can be described in more detail below. Other methods for obtaining final compounds of formula (I) are described in the examples.

Compounds of formula (I) can be prepared by reacting intermediates of formula (IV) such that W is for example halo, such as fluoro, chloro, bromo or iodo, or sulfonyloxy groups such as methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like. Can be prepared by reacting with an intermediate of formula (V) which is a suitable leaving group. The reaction may be, for example, an alcohol such as methanol, ethanol, 2-methoxyethanol, propanol, butanol, etc .; an ether such as 1,4-dioxane, a mixture of hydrochloric acid / 1,4-dioxane, 1,1′-oxybispropane, etc. Ketones such as 4-methyl-2-pentanone; or reaction inert solvents such as N, N-dimethylformamide, nitrobenzene, acetonitrile, acetic acid and the like, or mixtures thereof. It is liberated during the course of the reaction using the addition of a suitable base such as alkali or alkaline earth metal carbonates or organic carbonates or organic bases such as triethylamine or sodium carbonate or N, N-diisopropylethanamine. Acid can be neutralized. A small amount of a suitable metal iodide, such as sodium or potassium iodide, can be added to accelerate the reaction. Agitation can increase the rate of reaction. The reaction can be conveniently carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture, and, if desired, the reaction can be carried out at an elevated pressure.

A compound of formula (Ia) and a compound of formula (I) where X is CH ₂ referred to herein are those wherein X, referred to herein as a compound of formula (Ib), is C ( = O) can be prepared by reacting a compound of formula (I) with lithium aluminum hydride or BH _{3 in} a suitable solvent such as tetrahydrofuran.

  A compound of formula (Ia) is prepared from a suitable reagent such as sodium borohydride, eg sodium borohydride, or a polymer-supported cyanoborohydride in a suitable solvent such as an alcohol, eg methanol. It can also be prepared by reacting the appropriate carboxaldehyde of formula (VI) with an intermediate of formula (VII) in the presence.

  In the same way, a compound of formula (I) wherein t is 1, referred to herein as a compound of formula (Ic), is an intermediate of formula (IV) of formula HC (═O) Z It can be prepared by reacting with a suitable carboxaldehyde.

  A compound of formula (I) wherein s is 1, referred to herein as a compound of formula (Id), is prepared by reacting an intermediate of formula (VIII) with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran. It can be produced by reacting.

A compound of formula (I) wherein R ⁴ is —CH ₂ —OH, referred to herein as a compound of formula (Ie), is an intermediate of formula (XXIV) in a suitable solvent such as tetrahydrofuran. It can be produced by reacting with lithium aluminum hydride.

  Compounds of formula (III) may be prepared by converting the intermediate of formula (XIX) in the presence of a strong acid, such as HCl, in a suitable solvent such as tetrahydrofuran.

A compound of formula (III), referred to herein as a compound of formula (III-a), where s is 0 and R ³ is hydrogen, is an intermediate of formula (IV-c) herein. S is 0, R ³ is hydrogen,

An intermediate of formula (IV) in which R ⁹ is —CR ⁹ ═C <and R ⁹ together with R ²⁰ forms a direct bond, for example an alcohol such as methanol, ethanol, 2-methoxyethanol, propanol, Ethers such as 1,4-dioxane, 1,1′-oxybispropane; ketones such as 4-methyl-2-pentanone; or N
Prepared by reacting with an intermediate of formula (V) in which W is a suitable leaving group as defined above in a reaction inert solvent such as N, dimethylformamide, nitrobenzene, acetonitrile, acetic acid, etc. Can do. The addition of a suitable base such as an alkali or alkaline earth metal carbonate or an organic base such as triethylamine or sodium carbonate can be used to neutralize the acid liberated during the course of the reaction.

Compounds of formula (III), where R ⁶ is hydrogen, referred to herein as compounds of formula (III-b), are obtained by Fischer's indole synthesis starting from intermediates of formulas (XXII) and (XXIII). Can also be manufactured.

  The compounds of formula (I) and their intermediates can also be converted into each other via reactions known in the art or functional group transformations. Many such transformations have already been described above. Other examples are hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; hydrolysis of the amide to the corresponding carboxylic acid or amine; hydrolysis of the nitrile to the corresponding amide; on imidazole or phenyl Amino groups can be replaced by hydrogen by known diazotization reactions and subsequent substitution of diazo groups with hydrogen; alcohols can be converted to esters and ethers; primary amines can be converted to secondary or tertiary amines. The double bond can be hydrogenated to the corresponding single bond; the iodo group on the phenyl group can be converted to an ester group by carbon monoxide insertion in the presence of a suitable palladium catalyst; Etc.

An intermediate of formula (IV), referred to herein as an intermediate of formula (IV-a), wherein X is CH ₂ , m is 0, s is 0 and R ³ is hydrogen In the presence of a suitable catalyst such as Raney nickel or palladium on charcoal and a suitable reducing agent such as hydrogen in a suitable solvent such as methanol, ethanol, toluene, tetrahydrofuran or mixtures thereof. It can be prepared by a body-initiated nitro to amine reduction reaction. For compounds with 0 moieties suitable for catalytic hydrogenation purposes, Pt / C, optionally poisoned with thiophene, can be used. V ₂ O ₅ can be used as a cocatalyst. A suitable solvent for this reaction is tetrahydrofuran or toluene.

An intermediate of formula (IV), referred to herein as an intermediate of formula (IV-b), where X is C (= O), S is 0 and R ³ is hydrogen is N In the presence of suitable coupling reagents such as'-(ethylcarbonimidoyl) -N, N-dimethyl-1,3-propanediamine monohydrochloride (EDC) and 1-hydroxy-1H-benzotriazole (HOBT) Can be prepared by reacting an intermediate of formula (X) with an intermediate of formula (XI). The reaction can be carried out in a suitable solvent such as a mixture of dichloromethane and tetrahydrofuran in the presence of a base such as triethylamine.

  The intermediate of formula (VI) can be prepared by reacting the intermediate of formula (XII) with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran.

  The intermediate of formula (VIII) can be converted from the intermediate of formula (XIII) with the intermediate of formula (XIV) in the presence of 2-chloro-1-methylpyridinium iodide and triethylamine in a suitable solvent such as acetonitrile. It can be produced by reacting.

The intermediate of formula (IX) is heated in a suitable solvent such as dimethyl sulfoxide or toluene, preferably in the presence of a base such as NaHCO ₃ or N, N-diisopropylethanamine, optionally at a high temperature such as about 60 ° C. Wherein A is a suitable leaving group such as halo, for example fluoro, chloro, bromo or iodo, or C _1-6 alkyloxy, for example methyloxy, intermediate of formula (XVI) and formula (XV) It can be produced by reacting the body.

An intermediate of formula (XIII), referred to herein as an intermediate of formula (XVI-a), wherein R ²⁰ represents —CH ₂ —OH, is NaBH _{4 in} a suitable solvent such as an alcohol, eg methanol. Can be prepared by reducing the intermediate of formula (XXV) with a suitable reducing agent such as

  The intermediate of formula (XIII) can be prepared by converting the intermediate of formula (XVII) in the presence of sodium hydroxide and water in a suitable solvent such as ethanol.

  The intermediate of formula (XVII) is an intermediate of formula (XVIII) in which a suitable leaving group as defined above is replaced with an intermediate of formula (XV) in a suitable solvent such as diisopropylethylamine. It can be produced by reacting.

The intermediate of formula (XV), referred to herein as the intermediate of formula (XV-a), wherein R ¹ represents hydrogen, is a suitable catalyst such as Raney nickel, ammonia, and alcohols such as methanol It can be prepared by reacting an intermediate of formula (XXVI) in the presence of a suitable solvent.

  An intermediate of formula (XXVI) is prepared by reacting an intermediate of formula (XXVII) with sodium cyanide in a suitable solvent such as N, N-dimethylformamide where C represents a suitable counterion such as iodide. Can be produced.

The intermediate of formula (XXVI) in which R ⁴ or R ⁵ represents hydroxyC _1-6 alkyl (eg —CH (CH ₃ ) —OH or —C (CH ₃ ) ₂ —OH) is the corresponding aldehyde or ketone compound (Eg, —C (═O) H or —C (═O) —CH ₃ ) may be prepared by reaction with methylmagnesium chloride in a suitable solvent such as tetrahydrofuran.

An intermediate of formula (XXVI) in which R ⁴ or R ⁵ represents —C (═O) —CH ₃ is reacted with a suitable oxidizing reagent such as Dess-Martin reagent to give the corresponding —CH (CH ₃ ) — It can be produced from an OH compound.

  Intermediates of formula (XXVII) may be prepared from the corresponding secondary amine by reaction with a suitable alkylating agent such as methyl iodide in a suitable solvent such as an alcohol, for example ethanol.

  The intermediate of formula (IV-c) is an intermediate of formula (XX) in the presence of a metal catalyst such as Raney nickel and a suitable reducing agent such as hydrogen in a suitable solvent such as methanol or ethanol. It can be prepared by a starting nitro to amine reduction reaction.

The intermediate of formula (XX) is prepared in a suitable inert polar solvent such as an alcohol such as methanol, acetonitrile or DMF in the presence of a base such as MgO and an organopalladium catalyst such as Pd (OAc) ₂ . It can be prepared by an Heck reaction from an intermediate of formula (XXI) where D is a suitable halogen leaving group such as bromo or iodo.

  Intermediates of formula (XIX) or (XXIV) can be prepared according to the reactions described above for the preparation of compounds of formula (I) from intermediates of formula (IV) and (V).

  Some compounds of formula (I) and some of the intermediates may have at least one stereogenic center in their structure. Any such stereogenic center can exist independently in the R or S configuration.

  Some of the compounds of formula (I) and some of the intermediates of the present invention may contain asymmetric carbon atoms. Such compounds, prepared by the methods described above, can generally be enantiomers or racemic mixtures of diastereomers, which can be separated from each other according to resolution procedures known in the art. For example, diastereomers can be separated by physical methods such as selective crystallization, or by chromatographic techniques such as counter current distribution, liquid chromatography and similar methods. Enantiomers can be obtained by first converting the racemic mixture to a mixture of diastereomeric salts or compounds with a suitable resolving agent such as a chiral acid; then, for example, selective crystallization, supercritical liquid chromatography or chromatography. Physically separating the mixture of diastereomeric salts or compounds by graphic techniques such as liquid chromatography and similar methods; and finally, separating the separated diastereomeric salts or compounds with the corresponding enantiomers. It can be obtained from the racemic mixture by conversion to the body. Pure stereoisomers can also be obtained from the appropriate intermediates and starting pure stereoisomers, provided that the intervening reaction occurs stereospecifically.

  Compounds of formula (I), their pharmaceutically acceptable acid or base addition salts, solvates, N-oxides and stereoisomers are valuable because they inhibit the interaction between p53 and MDM2. Pharmacological properties.

  The term “MDM2” (Murine Double Minute 2) is used herein to mean a protein obtained as a result of expression of the mdm2 gene. Within the meaning of this term, MDM2 encompasses all proteins encoded by mdm2, their variants, their selective slice proteins and their phosphorylated proteins. In addition, as used herein, the term “MDM2” includes MDM2 analogs, eg, MDMX, also known as MDM4, and other animal MDM2 homologues and analogs, eg, human homolog HDDM2 or human analog HDMX To do.

  The term “inhibiting an interaction” or “inhibitor of interaction” prevents or reduces the direct or indirect association of one or more molecules, peptides, proteins, enzymes or receptors; or As used herein to mean preventing or reducing the normal activity of one or more molecules, peptides, proteins, enzymes or receptors.

The term “inhibitor of p53 interaction with MDM2” or “p53-MDM2 inhibitor” is C.I. 1 is used herein to describe agents that increase the expression of p53 in the assay described in 1. This increase includes, but is not limited to, the following mechanism of action: inhibiting the interaction between -p53 and MDM2,
-Direct association with either MDM2 or p53 protein;
-Interaction with upstream or downstream targets such as kinases or enzymatic activities involved in ubiquitination or SUMO modification;
-Isolation or transport of MDM2 and p53 to different cell compartments,
-Regulation of proteins associated with MDM2, such as but not limited to p63, p73, E2F-1, Rb, p21waf1 or cip1, HIF1α, Foxo3A, p14ARF,
Down-regulation or interference with MDM2 expression and / or MDM2 activity, such as but not limited to affecting its cellular localization, post-translational modification, nuclear export, ubiquitin ligase activity, or of MDM2 with the proteasome Interference with binding, modulating the interaction between MDM2 and the proteasome,
Direct or indirect stabilization of the p53 protein, for example by keeping it in its functional structural form or by preventing misfolding,
-Enhancing p53 expression or expression of p53 family members such as p63 and p73,
-E.g. (but not limited to) increasing p53 activity by increasing its transcriptional activity, and / or-genes and proteins of the p53 signaling pathway, e.g. (but not limited to) p21waf1, cip1, It can be caused by one or more of increasing the expression of MIC-1 (GDF-15), PIG-3, Bax, Puma, Noxa and ATF-3.

  Therefore, the present invention is particularly useful for the treatment of cancer or related diseases, to inhibit tumor growth, to inhibit the interaction between MDM2 and p53, and as a medicament for modulating the interaction between MDM2 and the proteasome. Disclosed are compounds of formula (I) for use in

  Furthermore, the present invention also relates to the use of a compound for the manufacture of a medicament for the treatment of disorders mediated by the interaction of p53 and MDM2, said compound being a compound of formula (I).

  As used herein, the term “treating” or “treatment” encompasses any treatment of a disease and / or condition in an animal, particularly a human, and (i) affects the disease and / or condition. Preventing the disease and / or condition from occurring in a subject that may be easy but not yet diagnosed as having it; (ii) inhibiting the disease and / or condition, ie, its occurrence (Iii) alleviating the disease and / or condition, ie causing regression of the disease and / or condition.

  The term "disorder mediated by the interaction of p53 and MDM2" refers to the interaction between MDM2 protein and p53 or other cellular proteins that induce apoptosis, induce cell death, or regulate the cell cycle It means any undesirable or harmful condition arising from.

  The invention relates to disorders mediated by the interaction of p53 and MDM2 by administering an effective amount of a compound of the invention to a subject in need of such treatment, such as a mammal (and more specifically a human). A method of treatment is also provided.

  The compounds of the present invention may have an antiproliferative effect in such cells even when the tumor cells lack functional p53. More specifically, the compounds of the invention may have an antiproliferative effect in tumors with wild type or mutant p53 and / or tumors that overexpress MDM2.

  Accordingly, the present invention also provides a method of inhibiting tumor growth by administering an effective amount of a compound of the present invention to a subject in need of such treatment, such as a mammal (and more specifically a human).

Examples of tumors that include malignant lesions in adults and children that can be inhibited by the compounds of the present invention include, but are not limited to, lung cancer, pancreatic cancer, including small cell lung cancer and non-small cell lung cancer (eg, adenocarcinoma), Colon cancer (eg colorectal cancer such as colon adenocarcinoma and colon adenoma), esophageal cancer, oral squamous cell carcinoma, tongue cancer, gastric cancer, liver cancer, nasopharyngeal cancer, lymphoid hematopoietic tumor (eg acute lymphocytic) Leukemia, B cell lymphoma, Burkitt lymphoma), non-Hodgkin lymphoma (eg mantle cell lymphoma), Hodgkin disease, myeloid leukemia (eg acute myeloid leukemia (AML) or chronic myeloid leukemia (CML)), acute lymphocytic leukemia , Chronic lymphocytic leukemia (CLL), follicular thyroid carcinoma, myelodysplastic syndrome (MDS), tumor of mesenchymal origin, soft tissue sarcoma, liposarcoma, gastrointestinal stromal sarcoma Malignant peripheral nerve sheath tumor (MPNST), Ewing sarcoma, leiomyosarcoma, mesenchymal chondrosarcoma, lymphosarcoma, fibrosarcoma, rhabdomyosarcoma, melanoma, teratocarcinoma, neuroblastoma, brain tumor, glioma, skin Prostate cancer, including benign tumors (eg keratoacanthoma), breast cancer (eg advanced breast cancer), renal cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, progressive disease and hormone refractory prostate cancer Testicular cancer, osteosarcoma, head and neck cancer, epidermis cancer, multiple myeloma (for example, refractory multiple myeloma), and mesothelioma. Particular cancers that can be treated with the compounds of the invention are breast cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia (AML).

  The compounds of the invention can also be used for the treatment and prevention of inflammatory conditions.

  Accordingly, the present invention also provides a method of treating and preventing inflammatory conditions by administering an effective amount of a compound of the present invention to a subject in need of such treatment, such as a mammal (and more specifically a human). To do.

  The compounds of the present invention may also be used for the treatment of autoimmune diseases and conditions. By the term “autoimmune disease” is meant any disease in which an animal's immune system reacts adversely with self-antigens. By the term “self-antigen” is meant any antigen normally found in the animal body. Representative autoimmune diseases include, but are not limited to, Hashimoto's thyroiditis, Graves' disease, multiple sclerosis, pernicious anemia, Addison's disease, insulin-dependent diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), skin Myositis, Crohn's disease, Wegener's granulomatosis, antiglomerular basement membrane disease, antiphospholipid syndrome, 25 herpes zoster, allergic encephalomyelitis, glomerulonephritis, membranous glomerulonephritis, Goodpasture syndrome, Lambert Mention may be made of Eaton myasthenia syndrome, myasthenia gravis, bullous pemphigoid, multiglandular endocrine disorders, Reiter's disease and systemic stiffness syndrome.

  Accordingly, the present invention also provides a method of treating autoimmune diseases and conditions by administering an effective amount of a compound of the present invention to a subject in need of such treatment, such as a mammal (and more specifically a human). provide.

  The compounds of the present invention may also be useful in the treatment of diseases associated with conformationally unstable or misfolded proteins.

  Examples of diseases associated with conformationally unstable or misfolded proteins include, but are not limited to, cystic fibrosis (CFTR), Marfan syndrome (fibrillin), amyotrophic lateral sclerosis ( Superoxide dismutase), scurvy (collagen), maple syrup urine disease (α-keto acid dehydrogenase complex), osteogenesis imperfecta (type I procollagen proα), Creutzfeldt-Jakob disease (prion), Alzheimer's disease (β-amyloid), familial amyloidosis (lysozyme), cataract (crystallin), familial hypercholesterolemia (LDL receptor), I-antitrypsin deficiency, Tay-Sachs disease (β-hexosaminidase) , Retinitis pigmentosa (rhodopsin) and fairies (insulin receptor) Kill.

Accordingly, the present invention provides conformational instability or misfolding by administering an effective amount of a compound of the present invention to a subject in need of such treatment, such as a mammal (and more specifically a human). Also provided are methods of treating diseases associated with the purified proteins.

  In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes.

  To produce a pharmaceutical composition of the invention, an effective amount of a compound of the invention as an active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, the carrier being in the form of the formulation desired for administration. It can take various forms depending on These pharmaceutical compositions are desirably in unit dosage forms suitable for administration preferably orally, rectally, transdermally or by parenteral injection. For example, in the production of compositions in oral dosage forms, for oral liquid formulations such as suspensions, syrups, elixirs and solutions, eg water, glycols, oils, alcohols etc .; In the case of agents and tablets, any conventional pharmaceutical medium can be used, such as solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants and the like.

  Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually include at least a majority of sterile water, but may include other ingredients to aid solubility, for example. For example, an injectable solution can be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of saline and a glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in combination with a small proportion of any suitable additive. Objects do not cause significant harmful effects on the skin. Said additives can facilitate the administration of the active ingredient to the skin and / or can help to produce the desired composition. These compositions can be administered in various ways, for example as transdermal patches, spot-on agents, ointments. It is especially useful to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. As used in the specification and claims herein, dosage unit forms refer to physically discrete units suitable as unit dosages, each unit being as desired with the pharmaceutical carrier required. Contains a predetermined amount of active ingredient calculated to produce a therapeutic effect. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, cachets, injectable solutions or suspensions, a teaspoon, table Such as a spoonful, and their separated multiples.

  It is especially useful to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. As used in the specification and claims herein, dosage unit forms refer to physically discrete units suitable as unit dosages, each unit being as desired with the pharmaceutical carrier required. Contains a predetermined amount of active ingredient calculated to produce a therapeutic effect. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, cachets, injectable solutions or suspensions, a teaspoon, table Such as a spoonful, and their separated multiples.

  The compounds of the present invention interact between MDM2 and p53 or other cellular proteins that induce apoptosis, induce cell death, regulate the cell cycle, and regulate tumor cell migration or invasion or metastasis. It is administered in an amount sufficient to inhibit, specifically an amount sufficient to modulate the interaction between MDM2 and the proteasome.

The oncogenic ability of MDM2 is not only due to its ability to inhibit p53, but also due to its ability to modulate other tumor suppressor proteins, such as the retinoblastoma protein pRb and the closely related E2F1 transcription factor, p63, p73. It is determined.

  Accordingly, the compounds of the invention are administered in an amount sufficient to modulate the interaction between MDM2 and the E2F1 transcription factor.

  One skilled in the art can readily determine the effective amount from the test results presented below. In general, it is contemplated that a therapeutically effective amount can be from 0.005 mg / kg to 100 mg / kg body weight, and especially from 0.005 mg / kg to 10 mg / kg body weight. It may be appropriate to administer the required dose as 1, 2, 3, 4 or more sub-doses at appropriate intervals throughout the day. The sub-dose may be formulated as a unit dosage form containing, for example, 0.5 to 500 mg, in particular 1 mg to 500 mg, more specifically 10 mg to 500 mg of active ingredient per unit dosage form.

  Depending on the mode of administration, the pharmaceutical composition is preferably 0.05 to 99% by weight, more preferably 0.1 to 70% by weight, even more preferably 0.1 to 50% by weight. Up to 1 to 99.95% by weight, more preferably 30 to 99.9% by weight, even more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier. All percentages are based on the total weight of the composition.

  As another aspect of the invention, the combination of a p53-MDM2 inhibitor with another anticancer agent is envisaged, particularly for use as a pharmaceutical, and more specifically in the treatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of the invention may advantageously be used in combination with one or more other drugs, more specifically other anticancer drugs or adjuvants in cancer therapy. Examples of anti-cancer agents or adjuvants (supporting agents in treatment) include, but are not limited to, platinum coordination compounds such as cisplatin, optionally in combination with amifostine, carboplatin or oxaliplatin;
A taxane compound, such as paclitaxel, paclitaxel protein binding particles (Abraxane ^™ ) or docetaxel;
A camptothecin compound, for example a topoisomerase I inhibitor such as irinotecan, SN-38, topotecan, topotecan hydrochloride;
An anti-tumor epipodophylrodoxin or podophyllotoxin derivative, for example a topoisomerase II inhibitor such as etoposide, etoposide phosphate or teniposide;
An anti-tumour vinca alkaloid, such as vinblastine, vincristine or vinorelbine;
An anti-tumor nucleoside derivative, such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hydrochloride, capecitabine, cladribine, fludarabine, nelarabine;
-Nitrogen mustard or nitrosourea, such as cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, artretamine, busulfan, dacarbazine, estramustine, and in some cases ifosfamide, pipobroman, procarbazine in combination with mesna , Alkylating drugs such as streptozocin, terozolomide, uracil;
An antitumor anthracycline derivative such as daunorubicin, optionally in combination with dexrazoxane, doxorubicin, doxyl, idarubicin, mitoxantrone, epirubicin, epirubicin hydrochloride, valrubicin;
A molecule that targets the IGF-1 receptor, such as picropodophyllin;
A tetracalcine derivative, such as tetrocalcin A;
A glucocorticoid, such as prednisone;
-Antibodies such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetane, CNTsumab, tofetumomab ;
An estrogen receptor antagonist or a selective estrogen receptor modulator, or an inhibitor of estrogen synthesis, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;
An aromatase inhibitor such as exemestane, anastrozole, letrazole, test lactone and borozole;
-Differentiation agents such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism inhibitors (RAMBA), for example Actein;
A DNA methyltransferase inhibitor, such as azacitidine or decitabine;
An antifolate, such as premetrexed disodium; an antibiotic such as antimycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, pricamycin, mitramycin;
An antimetabolite such as clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;
-Apoptosis inducers and anti-angiogenic agents such as Bcl-2 inhibitors such as YC 137, BH 312, ABT 737, Gossypol, HA 14-1, TW37 or decanoic acid;
A tubulin binding agent such as combrestatin, colchicine or nocodazole;
-Kinase inhibitors (eg EGFR (epidermal growth factor receptor) inhibitors, MTKI (multi target kinase inhibitor), mTOR inhibitors) such as flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib Tosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;
A farnesyltransferase inhibitor, eg tipifanib;
-Histone deacetylase (HDAC) inhibitors such as sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A, Vorinostat;
-Inhibitors of the ubiquitin-proteasome pathway, such as PS-341, MLN. 41 or bortezomib;
-Yongdelis;
A telomerase inhibitor, such as telomestatin;
A matrix metalloproteinase inhibitor, such as batimastat, marimastat, purinostat or metastat.
-Recombinant interleukins such as aldesleukin, denileukin diftitox, interferon α2a, interferon α2b, peginterferon α2b
-MAPK inhibitors-retinoids such as alitretinoin, bexarotene, tretinoin-arsenite-asparaginase-steroids such as drmostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), Dexamethasone-gonadotropin-releasing hormone agonist or antagonist such as abarelix, goserelin acetate, histrelin acetate, leuprolide acetate-salidomide, lenalidomide-mercaptopurine, mitotan, pamidronic acid, pegademase, pegaspargase, rasburicase-BH3 Mimetics such as ABT-737
-MEK inhibitors such as PD98059, AZD6244, CI-1040
-Colony stimulating factor analogues such as filgrastim, pegfilgrastim, salgramostim; erythropoietin or analogues thereof (eg darbepoetin alpha); interleukin 11; oprelbekin; zoledonate; zoledronic acid; fentanyl; bisphosphonate; .

  As stated above, the compounds of the present invention also have therapeutic applications in the sensitization of tumor cells to radiation therapy and chemotherapy.

  Hence, the compounds of the present invention can be used as “radiation sensitizers” and / or “chemotherapy sensitizers” or as alternative “radiation sensitizers” and / or “chemotherapy sensitizers”. Can be given together.

  The term “radiation sensitizer” as used herein is therapeutically effective to increase the sensitivity of cells to ionizing radiation and / or facilitate the treatment of diseases that are treatable with ionizing radiation. Defined as a molecule administered to an animal in an amount, preferably a low molecular weight molecule.

  The term “chemosensitizer” as used herein is therapeutically effective to increase the sensitivity of cells to chemotherapy and / or facilitate the treatment of diseases that can be treated with chemotherapy. It is defined as a molecule, preferably a low molecular weight molecule, that is administered to an animal in any amount.

  Effects of radiation sensitizers including hypoxic cell radiation sensitizers that mimic oxygen under hypoxia or behave like bioreductants (eg 2-nitroimidazole compounds and benzotriazine compounds) Several mechanisms of mode have been suggested in the literature; non-hypoxic cell radiation sensitizers (eg, halogenated pyrimidines) can be analogs of DNA bases and preferentially coalesce with cancer cell DNA; And thereby promote radiation-induced cleavage of DNA molecules and / or prevent normal DNA repair mechanisms; and a variety of other potential mechanisms of action of radiation sensitizers in the treatment of disease have been postulated.

  Many cancer treatment protocols currently use radiation sensitizers with x-ray radiation. Examples of x-ray activated radiation sensitizers include but are not limited to: metronidazole, misonidazole, desmethylmisonazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9. RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and their therapeutically effective analogs and Derivatives can be mentioned.

  Photodynamic therapy (PDT) for cancer uses visible light as a radiation activator for sensitizers. Examples of photodynamic radiation sensitizers include, but are not limited to, the following: Mention may be made of naphthalocyanine, phthalocyanine, zinc phthalocyanine and their therapeutically effective analogues and derivatives.

  Radiation sensitizers include, but are not limited to, compounds that promote uptake of radiation sensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and / or oxygen to target cells; additional One or more other therapeutically effective compounds that may include chemotherapeutic agents that act on the tumor with or without radiation; or other therapeutically effective compounds for treating cancer or other diseases. Can be administered with any compound.

  Chemotherapeutic sensitizers include, but are not limited to, compounds that promote uptake of chemotherapeutic agents into target cells; compounds that control the flow of therapeutic agents, nutrients and / or oxygen to target cells; May be administered with a therapeutically effective amount of one or more other compounds, which may include chemotherapeutic agents or other therapeutically effective compounds for treating cancer or other diseases. Calcium antagonists, such as verapamil, have been found useful with anticancer agents to establish chemosensitivity in tumor cells resistant to acceptable chemotherapeutic agents and to enhance the effectiveness of such compounds in drug-sensitive malignancies. Has been.

  In view of their useful pharmacological properties, the components of the combination of the present invention, i.e. one or more other drugs and the p53-MDM2 inhibitor of the present invention, are in various pharmaceutical forms for administration purposes. Can be prescribed. The ingredients may be formulated separately in individual pharmaceutical compositions or in a single pharmaceutical composition containing all ingredients.

  The present invention thus also relates to a pharmaceutical composition comprising one or more other agents and a p53-MDM2 inhibitor of the present invention together with a pharmaceutical carrier.

  The invention further relates to the use of the combination of the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells.

  The present invention further provides a combination formulation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer, the p53-MDM2 inhibitor of the present invention as a first active ingredient, and 1 as a further active ingredient. It relates to products containing seeds or more anticancer agents.

  One or more other agents and the p53-MDM2 inhibitor may be administered simultaneously (eg, in separate or single compositions) or sequentially in either order. In the latter case, two or more compounds can be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. The preferred method and order of administration of each component of the combination, as well as the respective dosage and dosing regimen, are specific other drugs being administered and p53-MDM2 inhibitors, their route of administration, the particular tumor being treated, It will be appreciated that it may depend on the particular host being treated as well. Optimal dosing methods and sequences and dosages and dosing schedules can be readily determined by one skilled in the art using conventional methods and in view of the information presented herein.

The weight ratio of the compound of the invention and one or more other anticancer agents when given as a combination can be determined by one skilled in the art. The ratio and exact dosage and frequency of administration are determined by the particular compound of the invention and the other anticancer agent (s) used, the particular condition being treated, as known to those skilled in the art. The severity of the condition at hand, the age, weight, sex, diet, time of administration and general physical condition of the particular patient, the mode of administration, and other medications that the individual may be taking. It is further apparent that the effective daily dose can be reduced or increased depending on the response of the subject being treated and / or depending on the evaluation of the physician prescribing the compound of the invention. Specific weight ratios of the present compound of formula (I) and another anticancer agent are 1/10 to 10/1, more specifically 1/5 to 5/1, and even more specifically 1/3. Can range from 1 to 3/1.

The platinum coordination compound is advantageously administered at a dosage of 1 to 500 mg per square meter of body surface area (mg / m ² ), for example 50 to 400 mg / m ² , especially about 75 mg / m ² per course of treatment for cisplatin. The dose is about 300 mg / m ² and for carboplatin.

The taxane compound is advantageously administered at a dosage of 50 to 400 mg per square meter of body surface area (mg / m ² ), for example 75 to 250 mg / m ² , especially about 175 to 250 mg / m ² per treatment course for paclitaxel. The dose is administered at about 75 to 150 mg / m ² for docetaxel.

The camptothecin compound is advantageously administered at a dosage of 0.1 to 400 mg per square meter of body surface area (mg / m ² ), for example 1 to 300 mg / m ² , especially about 100 to 350 mg / m ² per treatment course for irinotecan. And about 1-2 mg / m ² for topotecan.

The anti-tumor podophyllotoxin derivative is advantageously administered at a dosage of 30 to 300 mg per square meter of body surface area (mg / m ² ), for example 50 to 250 mg / m ² , especially about 35 to 100 mg per course of treatment for etoposide. / M ² dosage, and about 50 to 250 mg / m ² for teniposide.

The antineoplastic vinca alkaloid is advantageously administered at a dosage of ² to 30 mg (mg / m ² ) per square meter of body surface area, especially about 3 to 12 mg / m ² per course of treatment for vinblastine, about vincristine. It is administered at a dosage of 1 to 2 mg / m ^{2 and} a dosage of about 10 to 30 mg / m ² for vinorelbine.

The anti-tumor nucleoside derivative is advantageously administered at a dosage of 200 to 2500 mg per square meter of body surface area (mg / m ² ), for example 700 to 1500 mg / m ² , especially 200 to 500 mg / m 2 per 5-FU treatment course. ² dosages, a dosage of about 800 to 1200 mg / m ² for gemcitabine, and about 1000 to 2500 mg / m ² for capecitabine.

Alkylating agents such as nitrogen mustard or nitrosourea is advantageously from 100 per square meter of body surface area 500mg (mg ^{/ m} 2), for example, 120 to a dosage of 200 mg / ^{m 2,} inter alia, cyclophosphamide A dosage of about 100 to 500 mg / m ² per course of treatment, a dosage of about 0.1 to 0.2 mg / kg for chlorambucil, a dosage of about 150 to 200 mg / m ² for carmustine, and about 100 to about lomustine. Administer at a dosage of 150 mg / m ² .

The antineoplastic anthracycline derivative is advantageously administered at a dosage of 10 to 75 mg per square meter of body surface area (mg / m ² ), for example 15 to 60 mg / m ² , especially about 40 to 75 mg / per treatment course for doxorubicin. dosage of m ^2, in a dosage of about 25 to about daunorubicin 45 mg / ^{m 2,} and about 10 to about idarubicin is administered at a dosage of 15 mg / ^{m 2.}

Antiestrogens are advantageously administered at a dosage of about 1 to 100 mg per day, depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally at a dosage of 5-50 mg, preferably 10-20 mg twice a day, and the treatment is continued for a time sufficient to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally at a dosage of about 60 mg once a day, continuing the treatment for a time sufficient to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally once daily at a dosage of about 1 mg. Droloxifene is advantageously administered orally once daily at a dosage of about 20-100 mg. Raloxifene is advantageously administered orally once daily at a dosage of about 60 mg. Exemestane is advantageously administered orally once daily at a dosage of about 25 mg.

The antibody is advantageously administered at a dosage of about 1 to 5 mg (mg / m ² ) per square meter of body surface area, or as known in the art if different. Trastuzumab is advantageously administered at a dosage of 1 to 5 mg per square meter of body surface area (mg / m ² ), especially 2 to 4 mg / m ² per course of treatment.

  These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.

  The compounds of formula (I), their pharmaceutically acceptable acid addition salts and stereoisomers are labeled compounds and / or p53 and / or MDM2 and / or other molecules, peptides, proteins, enzymes or receptors Valuable diagnostic properties because they can be used to detect or identify the interaction of p53 and MDM2 in a biological sample comprising detecting or measuring the formation of a complex between Can have.

The detection or identification method may use a compound labeled with a labeling agent such as a radioisotope, an enzyme, a fluorescent substance, a luminescent substance, and the like. Examples of radioisotopes include ¹²⁵ I, ¹³¹ I, ³ H and ¹⁴ C. Enzymes are usually detectable by conjugation of an appropriate substrate, which in turn catalyzes a detectable reaction. Examples thereof include, for example, β-galactosidase, β-glucosidase, alkaline phosphatase, peroxidase and malate dehydrogenase, preferably horseradish peroxidase. Luminescent substances include, for example, luminol, luminol derivatives, luciferin, aequorin and luciferase.

  A biological sample can be defined as body tissue or fluid. Examples of body fluids are cerebrospinal fluid, blood, plasma, serum, urine, sputum, saliva and the like.

  The following examples illustrate the invention.

Under the experimental part, the term “DIPEA” means N-ethyl-N- (1-methylethyl) -2-propanamine, “K ₂ CO ₃ ” means potassium carbonate, “CH ₂ Cl “ ₂ ” means dichloromethane, “CH ₃ OH” means methanol, “MgSO ₄ ” means magnesium sulfate, “NaHCO ₃ ” means monosodium carbonate, “DMSO” means dimethyl sulfoxide. Means “MP” means melting point, “CH ₃ CN” means acetonitrile, “EtOAc” means ethyl acetate, “DIPE” means diisopropyl ether, “DMF” means N, N- dimethylformamide means, "THF" means tetrahydrofuran, _"V 2 _{O 5} 'means vanadium oxide,' NaBH ₄ 'water Of means sodium boron (-1), "NaCl" means sodium chloride, "EtOH" means ethanol, _"NH 4 OH" means ammonium hydroxide. Column chromatography on Sunfire was performed by Waters Corp. (Reverse phase HPLC using a C18 bonded silica stationary phase column Sunfire ^™ from (Milford, Mass.).

A. Intermediate production
Example A1
a) Production of intermediate 1

A mixture of 1,2,3-trifluoro-5-nitrobenzene (0.0037 mol), 1H-indole-3-ethanamine (0.0037 mol) and DIPEA (0.0189 mol) was stirred at 120 ° C. for 18 hours and then at room temperature. Cooled to 10%, poured into 10% aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ / CH ₃ OH (small amount). The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated till dryness, yielding 1.3 g (> 100%) of intermediate 1.
b) Production of intermediate 2

A mixture of intermediate 1 (0.0037 mol) and 10% Pd / C (0.13 g) in toluene (50 ml) was hydrogenated at ambient temperature at room temperature for 3 days and then filtered through celite. The filtrate was evaporated to dryness. The residue was dissolved in _CH 2 Cl _2. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness yielding 1.2 g (> 100%) of intermediate 2.

Example A2
a) Production of intermediate 3

2-Chloro-5-nitro-1,3-bis (trifluoromethyl) benzene (0.002 mol), 1H-indole-3-ethanamine (0.0024 mol) and NaHCO ₃ (0.0026 mol) in DMSO (4 ml). ) Was stirred at 100 ° C. for 48 hours, then cooled to room temperature and poured into H ₂ O. The precipitate was filtered, washed with diethyl ether and dried, yielding 0.41 g (49%) of intermediate 3 (MP: 152 ° C.).
b) Production of intermediate 4

A mixture of intermediate 3 (0.0008 mol) and Raney nickel (0.36 g) in CH ₃ OH (10 ml) was hydrogenated at atmospheric pressure at room temperature for 18 hours and then filtered through celite. The filtrate was evaporated to dryness. The residue was dissolved in _CH 2 Cl _2. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated till dryness, yielding 0.32 g (96%) of intermediate 4.

Example A3
a) Production of intermediate 5a

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0.0048 mol), 1H-indole-3-ethanamine (0.0048 mol) and NaHCO ₃ (0.0057 mol) in DMSO (10 ml) was added at 60 ° C. At rt overnight and cooled to room temperature. Ice water was added. The mixture was extracted with EtOAc. The organic layer was decanted, dried (MgSO ₄ ), filtered off and the solvent was evaporated until dryness. The residue was crystallized from CH ₃ CN / DIPE. The precipitate was filtered off and dried, yielding 1.03 g (62%) of intermediate 5a (MP: 98 ° C.).
b) Production of intermediate 6a

A large mixture of Intermediate 5a (0.0027 mol) and 5% Pt / C (0.1 g) in V ₂ O ₅ (0.01 g), 4% thiophene solution in DIPE (0.1 ml) and THF (20 ml) was added. Hydrogenated at room temperature under atmospheric pressure for 18 hours. The catalyst was removed by filtration. The filtrate was evaporated to dryness, yielding 0.91 g (100%) of intermediate 6a.
c) Production of intermediate 5b

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0.0048 mol), 1H-indole-3-ethanamine (0.004 mol) and NaHCO ₃ (0.0048 mol) in DMSO (10 ml) was added at 60 ° C. At rt overnight and cooled to room temperature. Ice water was added. The precipitate was filtered, washed with CH ₃ CN and dried, yielding 0.48 g (28%) of intermediate 5b (MP: 147 ° C.).
d) Production of intermediate 6b

A large mixture of Intermediate 5b (0.0013 mol) and 5% Pt / C (0.05 g) in V ₂ O ₅ (0.005 g), 4% thiophene solution in DIPE (0.05 ml) and THF (10 ml) was added. Hydrogenated at room temperature under atmospheric pressure for 18 hours and then filtered. The filtrate was evaporated to dryness, yielding 0.48 g (100%) of intermediate 6b.
e) Production of intermediate 5c

Of 1,3-dichloro-2-fluoro-5-nitrobenzene (0.0048 mol), 1H-indole-6-methoxy-3-ethanamine (0.0048 mol) and NaHCO ₃ (0.0057 mol) in DMSO (10 ml). The mixture was stirred at 60 ° C. overnight and cooled to room temperature. Ice water was added. The precipitate was filtered, washed with CH ₃ CN and the solvent evaporated to dryness, yielding 1.2 g (66%) of intermediate 5c (MP: 116 ° C.).
f) Production of intermediate 6c

A large mixture of Intermediate 5c (0.0031 mol) and 5% Pt / C (0.12 g) in V ₂ O ₅ (0.012 g), 4% thiophene solution in DIPE (0.12 ml) and THF (25 ml) was added. Hydrogenated at room temperature under atmospheric pressure for 18 hours, then filtered through celite. The filtrate was evaporated to dryness, yielding 1.2 g (100%) of intermediate 6c.

Example A4
a) Production of intermediate 7a

A mixture of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0.0026 mol), 1H-indole-3-ethanamine (0.0026 mol) and NaHCO ₃ (0.0032 mol) in DMSO (5 ml). Stir at 60 ° C. overnight and cool to room temperature. Ice water was added. The precipitate was filtered off, washed with CH ₃ CN and dried, yielding 0.54 g (62%) of intermediate 7a (MP: 146 ° C.).
b) Production of intermediate 8a

A large mixture of intermediate 7a (0.0012 mol) and 5% Pt / C (0.049 g) in V ₂ O ₅ (0.005 g), 4% thiophene solution in DIPE (0.049 ml) and THF (10 ml) Hydrogenated at room temperature under atmospheric pressure for 18 hours. The catalyst was removed by filtration. The filtrate was evaporated to dryness, yielding 0.36 g (100%) of intermediate 8a.
c) Production of intermediate 7b

1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0.0026 mol), 1H-indole-7-methyl-3-ethanamine (0.0026 mol), NaHCO ₃ (0.0032 mol) in DMSO (5 ml). ) Was stirred at 60 ° C. overnight and cooled to room temperature. Ice water was added. The precipitate was filtered off, washed with CH ₃ CN and the solvent evaporated to dryness, yielding 0.53 g (58%) of intermediate 7b (MP: 171 ° C.). d) Production of intermediate 8b

A large mixture of intermediate 7b (0.0014 mol) and 5% Pt / C (0.05 g) in V ₂ O ₅ (0.005 g), 4% thiophene solution in DIPE (0.05 ml) and THF (15 ml) Hydrogenated at room temperature under atmospheric pressure for 18 hours, then filtered through celite. The filtrate was evaporated to dryness, yielding 0.49 g (100%) of intermediate 8b.

Example A5
a) Production of intermediate 9

NaBH ₄ (0.024 mol) was added in portions at 5 ° C. to a solution of 4-bromo-5-fluoro-2-nitrobenzaldehyde (0.02 mol) in CH ₃ OH (50 ml). The mixture was stirred at room temperature for 2 hours. Saturated aqueous NaCl was added. The mixture was extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness, yielding 5 g (100%) of intermediate 9.
b) Production of intermediate 10

A mixture of intermediate 9 (0.01 mol), 1H-indole-3-ethanamine (0.01 mol) and NaHCO ₃ (0.012 mol) in DMSO (25 ml) was stirred at 60 ° C. overnight and then cooled to room temperature. . Ice and water were added. The precipitate was filtered off, washed with CH ₃ CN and dried, yielding 1.77 g (45%) of intermediate 10.
c) Production of intermediate 11

A mixture of intermediate 10 (0.0045 mol), 5% Pt / C (0.18 g) and V ₂ O ₅ (0.02 g) in 4% thiophene solution (0.18 ml) and THF (50 ml) was atmospheric pressure. Hydrogenated at room temperature for 48 hours, then filtered through celite. The filtrate was evaporated to dryness, yielding 1.7 g (100%) of intermediate 11.

Example A6
a) Production of intermediate 12

A mixture of 1-fluoro-2-methyl-4-nitrobenzene (0.0103 mol), 7-methyl-1H-indole-3-ethanamine (0.0103 mol) and DIPEA (0.0515 mol) was stirred at 120 ° C. for 18 hours. Then cooled to room temperature, diluted with CH ₂ Cl ₂ / CH ₃ OH (small amount) and washed with 10% aqueous K ₂ CO ₃ solution. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (4.1 g) was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ / cyclohexane 70/30; 15-35 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.45 g (45%) of intermediate 12.
b) Production of intermediate 13

A mixture of intermediate 12 (0.0045 mol) and 5% Pt / C (0.15 g) in toluene (40 ml) was hydrogenated at room temperature under 3 bar pressure for 18 hours and then filtered. The filtrate was evaporated to dryness, yielding 1.25 g (100%) of intermediate 13.
c) Production of intermediate 14

Intermediate 13 (0.04 mol) in CH ₃ CN / EtOH (150 ml), (7S) -4-chloro-6,7-dihydro-5H-cyclopenta [b] pyridin-7-ol (0.0044 mol), A solution of 4M HCl / dioxane (2 ml) was stirred at 65 ° C. over the weekend. 10% aqueous K ₂ CO ₃ and EtOAc were added. The mixture was extracted. The organic layer was separated, dried (MgSO ₄ ), filtered off and the solvent was evaporated. The residue (23 g) was purified by column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 93/7/1). The pure fractions were collected and the solvent was evaporated. The residue (14.2 g, 85%) was crystallized from CH ₃ CN. The precipitate was filtered off and dried, yielding 10.4 g (63%) of intermediate 14.

Example A7
a) Production of intermediate 15

A mixture of 1-fluoro-2,3-dimethyl-4-nitrobenzene (0.003 mol), 1H-indole-3-ethanamine (0.0036 mol) and NaHCO ₃ (0.0039 mol) in DMSO (4 ml) was added at 100 ° C. For 3 days and then cooled to room temperature. H ₂ O was added. The precipitate was filtered, washed with EtOH and then with diethyl ether and dried. A portion of this fraction was dried under vacuum at 60 ° C. for 18 hours, yielding 0.052 g of intermediate 15 (MP: 178 ° C.).
b) Production of intermediate 16

A mixture of intermediate 15 (0.0022 mol) and Raney nickel (0.7 g) in CH ₃ OH / THF (90/10) (20 ml) was hydrogenated at atmospheric pressure at room temperature for 3 hours and then filtered through celite. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated till dryness, yielding 0.64 g (100%) of intermediate 16 (MP: 161 ° C.).

Example A8
a) Production of intermediate 17

Of 6-fluoro-2- (4-morpholinyl) -3-nitrobenzonitrile (0.002 mol), 1H-indole-3-ethanamine (0.002 mol) and NaHCO ₃ (0.0024 mol) in DMSO (5 ml). The mixture was stirred at 60 ° C. overnight and cooled to room temperature. Ice water was added. The precipitate was filtered off, washed with CH ₃ CN and dried, yielding 0.64 g (82%) of intermediate 17 (MP: 205 ° C.).
b) Production of intermediate 18

A large mixture of Intermediate 17 (0.0015 mol) and 5% Pt / C (0.06 g) in V ₂ O ₅ (0.01 g), 4% thiophene solution in DIPE (0.06 ml) and THF (10 ml) was added. Hydrogenated at room temperature under atmospheric pressure for 18 hours. The catalyst was removed by filtration. The filtrate was evaporated to dryness yielding 0.61 g (100%) of intermediate 18.

Example A9
a) Production of intermediate 19

A mixture of N- (4,5-difluoro-2-nitrophenyl) -acetamide (0.0023 mol), 1H-indole-3-ethanamine (0.0023 mol) and NaHCO ₃ (0.0028 mol) in DMSO (5 ml). Was stirred at 60 ° C. overnight and then cooled to room temperature. Ice and water were added. The precipitate was filtered off and dried, yielding 0.73 g (88%) of intermediate 19 (MP: 166 ° C.).
b) Production of intermediate 20

A mixture of intermediate 19 (0.002 mol) and Raney nickel (0.8 g) in CH ₃ OH (15 ml) was hydrogenated at room temperature for 4 hours at atmospheric pressure and then filtered through celite. The filtrate was evaporated to dryness. The residue was dissolved in _CH 2 Cl _2. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness, yielding 0.68 g (100%) of intermediate 20.

Example A10
a) Production of intermediate 21

Of 1,2-difluoro-3-methoxy-4-nitrobenzene (0.0074 mol), 7-methoxy-1H-indole-3-ethanamine (0.0074 mol) and NaHCO ₃ (0.0088 mol) in DMSO (15 ml). The mixture was stirred at 60 ° C. overnight and then cooled to room temperature. Ice and water were added. The precipitate was filtered, washed with CH ₃ CN and dried, yielding 2.27 g (85%) of intermediate 21 (MP: 164 ° C.).
b) Production of intermediate 22

A mixture of intermediate 21 (0.0058 mol), 5% Pt / C (0.21 g) and V ₂ O ₅ (0.021 g) in 4% thiophene solution (0.21 ml) and THF (30 ml) in DIPE. Hydrogenated at room temperature under atmospheric pressure for 48 hours, then filtered through celite. The filtrate was evaporated to dryness yielding 2.1 g (100%) of intermediate 22.

Example A11
Intermediate compounds comprising additional substituent (s) on the 1H-indol-3-yl ring can be converted to further substituted 1H-indole-3-ethanamines such as 2-methyl-1H-indole- Similar to the above reaction using 3-ethanamine, 7-methyl-1H-indole-3-ethanamine, 6-methoxy-1H-indole-3-ethanamine, or 7-methoxy-1H-indole-3-ethanamine Can be manufactured.

Example A12
a) Production of intermediate 23

A mixture of 1-methoxy-4-nitronaphthalene (0.0005 mol) and 1H-indole-3-ethanamine (0.0005 mol) in EtOH (3 ml) was stirred at 100 ° C. for 18 hours and then evaporated to dryness. . The residue (0.4 g) was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ 100). The pure fractions were collected and the solvent was evaporated, yielding 0.03 g (10%) of intermediate 23 (melting point: 211 ° C.).
b) Production of intermediate 24

A mixture of intermediate 23 (0.002 mol) and Raney nickel (0.7 g) in EtOH (50 ml) was hydrogenated at room temperature under 3 bar pressure for 18 hours and then filtered. The filtrate was evaporated to dryness. The residue (0.6 g) was purified by column chromatography over chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 99/1 / 0.1 to 97/3 / 0.3; 5 μm). . The pure fractions were collected and the solvent was evaporated, yielding 0.32 g (53%) of intermediate 24 (melting point: 148 ° C.).

Example A13
a) Production of intermediate 25

  Methyl iodide (0.0215 mol) was added dropwise to a solution of 3-[(dimethylamino) methyl] -1H-indole-7-carboxylic acid methyl ester (0.0215 mol) in EtOH (50 ml). The mixture was stirred at room temperature for 24 hours. The precipitate was filtered off and washed with EtOH, yielding 7.5 g of intermediate 25.

This product was used directly in the next reaction step.
b) Production of intermediate 26

  A mixture of intermediate 25 (0.02 mol) and sodium cyanide (0.026 mol) in DMF (75 ml) was stirred at 100 ° C. for 2 hours. Water was added. The precipitate was filtered off, yielding 2.2 g of intermediate 26.

This product was used directly in the next reaction step.
c) Production of intermediate 27

Raney nickel (37.485 mmol) was added to a solution of intermediate 26 and ammonia (7M, 25 ml) under nitrogen. The mixture was hydrogenated under 3 bar at room temperature for 5 hours. The crude product was filtered through celite and the solvent was evaporated, yielding 2.2 g of intermediate 27.
d) Production of intermediate 28

A mixture of intermediate 27 (0.00504 mol), 2,3 difluoro-6-nitroanisole (0.00504 mol) and sodium bicarbonate (0.00605 mol) in DMSO (110 ml) was heated at 60 ° C. overnight. The mixture was cooled to room temperature, after which ice water was added and the precipitate was filtered off, washed with CH ₃ CN and dried, yielding 0.860 g of intermediate 28.
e) Production of intermediate 29

A mixture of intermediate 28 (0.0022 mol) and Raney nickel (0.0147 mol) in CH ₃ OH (25 ml) was hydrogenated over the weekend at room temperature under atmospheric pressure of H ₂ . The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in CH ₂ Cl ₂ and the organic layer was dried over MgSO ₄ , filtered and evaporated to dryness, yielding 0.6 g of intermediate 29.

This product was used directly in the next reaction step.
f) Production of intermediate 30

CH ₃ CN / EtOH solution of intermediate 29 in (25 ml) 4M in dioxane in (0.000336mol) (0.00168mol), 4- chloro-6,7-dihydro -5H- cyclopenta [b] pyridin-7 A mixture of all (0.00168 mol) and hydrogen chloride was prepared. The mixture was stirred at 65 ° C. overnight. 10% aqueous K ₂ CO ₃ was added and the organic layer was extracted with CH ₂ Cl ₂ , dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.9 g) column chromatography over silica gel _{(eluent: CH 2 Cl 2 / CH 3} OH / NH 4 OH gradient 97/3 / 0.5; 90g 15~40μm ) was purified by. The pure fractions were collected and the solvent was evaporated. The residue was recrystallized in CH ₃ OH, yielding 0.160 g of intermediate 30.

Example A14
a) Production of intermediate 31

3-[(Dimethylamino) methyl] -1H-indole-7-carboxaldehyde (0.13 mol), iodomethane (0.14 mol) in EtOH (300 ml) was stirred at room temperature for 2 days. The precipitate was filtered off and dried, yielding 47 g of intermediate 31.
b) Production of intermediate 32

Intermediate 31 (136.5 mmol) and sodium cyanide (177.5 mmol) in DMF (400 ml) were stirred at room temperature for 2 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated. The residue was purified by high performance liquid chromatography (irregular SiOH 20-45 μm 1000 g MATREX / mobile phase: cyclohexane 70% ETOAc 30%). The pure fractions were collected and the solvent was evaporated, yielding 11.8 g of intermediate 32.
c) Production of intermediate 33

Methyl magnesium chloride (0.07 mol) was added dropwise to a solution of intermediate 32 (0.022 mol) in THF (50 ml). 10% aqueous NH ₄ Cl and EtOAc were added. The reaction mixture was extracted and the organic layer was separated, dried over MgSO ₄ , filtered and evaporated. The residue (2.9 g) was subjected to high performance liquid chromatography (irregular SiOH 20-45 μm 450 g MATREX / mobile phase: cyclohexane 60% EtOAc 4
0%). The pure fractions were collected and the solvent was evaporated, yielding 2 g of intermediate 33.
d) Production of intermediate 34

Dess-Martin periodinane (24.9 ml) was added dropwise at room temperature to a solution of intermediate 33 (10 mmol) in CH ₂ Cl ₂ (20 ml). The reaction mixture was stirred at room temperature for 1 h, then poured into ice water, filtered through celite and the filtrate extracted with CH ₂ Cl ₂ . The organic layer was separated, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue (2.8 g) was purified by column chromatography over silica gel (eluent: 60/40 cyclohexane / EtOAc). The pure fractions were collected and the solvent was evaporated, yielding 0.8 g of intermediate 34.
e) Production of intermediate 35

Methyl magnesium chloride (12.9 mmol) was added dropwise to a solution of intermediate 34 (4 mmol) in THF (5 ml) at 5 ° C. under N ₂ . The reaction mixture was stirred at room temperature for 30 minutes. A 10% aqueous NH ₄ Cl solution was carefully added at 5 ° C. EtOAc was added and the reaction mixture was extracted. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated. The residue (1.3g) was purified by column chromatography (eluent: 70/30 cyclohexane / EtOAc). The pure fractions were collected and the solvent was evaporated, yielding 0.8 g of intermediate 35.
f) Production of intermediate 36

A mixture of intermediate 35 (2.8 mmol), Raney nickel (0.6 g) in CH ₃ OH / NH ₃ (10 ml) was hydrogenated for 2 hours at room temperature under a pressure of 3 bar. The residue was filtered through celite, washed with CH ₂ Cl ₂ and the solvent was evaporated, yielding 0.7 g of intermediate 36.
g) Production of intermediate 37

A mixture of intermediate 36 (1.60 mmol), 2,3-difluoro-6-nitroanisole (1.76 mmol), sodium carbonate salt (1.92 mmol) in DMSO (5 ml) was heated at 60 ° C. overnight. The mixture was cooled to room temperature. Ice water was added. CH ₂ Cl ₂ was added. The reaction mixture was extracted and the organic layer was separated, dried over MgSO ₄ , filtered and concentrated.

The residue (0.8 g) was subjected to high performance liquid chromatography (irregular SiOH 15-45 μm).
(300 g MERCK / mobile phase: cyclohexane 70% EtOAc 30%). The pure fractions were collected and the solvent was evaporated, yielding 450 mg of intermediate 37.
h) Production of intermediate 38

Intermediate 37 (1.03 mmol), 5% Pt / C (0.1 g), V ₂ O ₅ (5 mg), 4% thiophene solution in DIPE (30 μl) in THF (20 ml) overnight at room temperature at atmospheric pressure. Hydrogenated. The reaction mixture was filtered through celite, washed with CH ₂ Cl ₂ and the filtrate was evaporated, yielding 0.33 g of intermediate 38.

B. Final compound production
Example B1
Production of Compound 11

A mixture of intermediate 2 (0.0012 mol), 4-bromopyridine hydrochloride (1: 1) (0.0012 mol) and DIPEA (0.001 mol) in CH ₃ CN (10 ml) was stirred at 65 ° C. for 18 hours. Then cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ solution and extracted with CH ₂ Cl ₂ / CH ₃ OH (small amount). The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.47 g) was purified by column chromatography over chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 97/3 / 0.3 to 91/9 / 0.9; 3.5 μm). Purified. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH ₃ CN. The precipitate is filtered off and dried to 0
. This yielded 163 g (36%) of compound 11 (MP: 164 ° C.).

  Compound numbers 12, 13 and 65 were prepared according to Example B1.

Example B2
a) Production of Compound 3

A mixture of intermediate 4 (0.0002 mol), 4-bromopyridine hydrochloride (1: 1) (0.0002 mol) and DIPEA (0.0002 mol) in CH ₃ CN (1 ml) and EtOH (0.5 ml). Stir at 65 ° C. for 18 hours. 4N HCl (0.2 eq) and dioxane (14 μl) were added. The mixture was stirred at 65 for 18 hours, then cooled to room temperature, diluted with CH ₂ Cl ₂ and washed with 10% aqueous K ₂ CO ₃ solution. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.24 g) was purified by column chromatography on Sunfire (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 100/0/0 to 93/7 / 0.7; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.073g, 57%) was crystallized from _CH 3 CN. The precipitate was filtered off and dried, yielding 0.039 g (30%) of compound 3 (MP: 187 ° C.).

Compound No. 4 was prepared according to Example B2a).
b) Production of compound 5

Intermediate 4 (0.0002 mol) and 4-chloro-6,7-dihydro-5H-cyclopenta [b] pyridine- in 4N HCl / dioxane (14 μl), CH ₃ CN (1 ml) and EtOH (0.5 ml) A mixture of 7-ol (0.0002 mol) was stirred at 65 ° C. for 18 hours. 4N HCl (0.2 eq) and dioxane (14 μl) were added. The mixture was stirred at 65 ° C. for 18 hours, then cooled to room temperature, diluted with CH ₂ Cl ₂ and washed with 10% aqueous K ₂ CO ₃ solution. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.14 g) was purified by column chromatography on Sunfire (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 100/0/0 to 92/8 / 0.8; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.072g, 50%) was crystallized from _CH 3 CN. The precipitate was filtered off and dried, yielding 0.049 g (30%) of compound 5 (MP: 178 ° C.).

Example B3
Production of Compound 14

A mixture of intermediate 2 (0.0012 mol), 4-chloro-2-pyridinemethanol (0.0012 mol) and 4N HCl / dioxane (0.0002 mol) in CH ₃ CN (10 ml) was stirred at 65 ° C. for 18 hours. Then cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ / CH ₃ OH (small amount). The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.52 g) was purified by column chromatography on chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 97/3 / 0.3 to 91/9 / 0.9; 3-5 μm). Purified. The pure fractions were collected and the solvent was evaporated. The residue (0.3g, 60%) was crystallized from _CH 3 CN. The precipitate was filtered off and dried, yielding 0.292 g (51%) of compound 14 as the hydrochloride salt (0.1.52 HCl, MP: 110 ° C.).

  Compound numbers 15, 16 and 60 were prepared according to Example B3. I want to be confirmed.

Example B4
a) Production of Compound 24

A mixture of intermediate 6a (0.0007 mol) and 4-chloro-2-pyridinemethanol (0.0007 mol) in 4N HCl / dioxane (0.0001 mol), CH ₃ CN (2.5 ml) and EtOH (1 ml). Stir at 65 ° C. for 18 hours. The mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ and washed with 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, dried (MgSO ₄ ), filtered and the solvent was evaporated to 15 ml. The residue was filtered off and dried, yielding 0.168 g (64%) of compound 24 (MP: 115 ° C.).
b) Production of Example 25

A mixture of intermediate 6b (0.0007 mol) and 4-chloro-2-pyridinemethanol (0.0007 mol) in 4N HCl / dioxane (0.0001 mol), CH ₃ CN (2 ml) and EtOH (0.8 ml). Stir at 65 ° C. for 18 hours. The mixture was cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The residue was filtered, washed with CH ₃ CN and dried, yielding 0.155 g (53%) of compound 25 (MP: 186 ° C.).

Compound numbers 26, 27 and 28 were prepared according to Example B4b).
c) Production of compound 31

A mixture of intermediate 6c (0.0008 mol) and 4-chloroquinoline (0.0009 mol) in 4N HCl / dioxane (0.0001 mol), CH ₃ CN (2.5 ml) and EtOH (1 ml) at 48 ° C. Stir for hours. The mixture was cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The precipitate was filtered, washed with CH ₃ CN and dried, yielding 0.266 g (71%) of compound 31 (MP: 175 ° C.).

  Compound numbers 29, 30 and 32 were prepared according to Example B4c).

Example B5
Preparation of compound number 17

Intermediate 2 (0.0012 mol), 4-chloro-6,7-dihydro-5H-cyclopenta [b] pyridin-7-ol (0.0012 mol) and 4N HCl / dioxane (0) in CH ₃ CN (10 ml) .0025 mol) was stirred at 65 ° C. for 18 hours, then cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ / CH ₃ OH (small amount). The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.54 g) was purified by column chromatography on chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 97/3 / 0.3 to 88/12 / 1.2; 3-5 μm). Purified. The pure fractions were collected and the solvent was evaporated. The residue (0.14g, 26%) was crystallized from _CH 3 CN. The precipitate was filtered off and dried, yielding 0.113 g (21%) of compound 17 (MP: 147 ° C.).

  Compound nos. 18, 19, 20, 21, 22, 23, 33, 34, 35, 36, 37 and 61 were prepared according to Example B5.

Example B6
a) Production of Compound 9

Intermediate 8a (0.0006 mol) and 4-chloro-6,7-dihydro-5H-cyclopenta in 4N HCl / dioxane (0.0001 mol), CH ₃ CN (2 ml) and CH ₃ OH (0.8 ml) [ b] A mixture of pyridin-7-ol (0.006 mol) was stirred at 65 ° C. for 18 hours and then cooled to room temperature. 3N HCl (0.0025 mol) was added. The mixture was stirred at 65 ° C. for 18 hours, cooled to room temperature, diluted with CH ₂ Cl ₂ and washed with 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.36 g) was purified by column chromatography over chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 98/2 / 0.2 to 90/10/1; 3.5 μm). . The pure fraction (0.14 g) was crystallized from CH ₃ CN. The precipitate was filtered off and dried, yielding 0.120 g (47%) of compound 9 (MP: 207 ° C.).

Compound numbers 7 and 8 were prepared according to Example B6a).
b) Production of compound 10

Intermediate 8b (0.0007 mol) and 4-chloro-6,7-dihydro-5H-cyclopenta in 4N HCl / dioxane (0.0001 mol), CH ₃ CN (2 ml) and CH ₃ OH (0.8 ml) [ b] A mixture of pyridin-7-ol (0.0008 mol) was stirred at 65 ° C. for 48 hours, then cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by column chromatography over chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 98/2 / 0.2 to 90/10/1; 3.5 μm). The pure fractions were collected and the solvent was evaporated until dryness. The residue was crystallized from CH ₃ CN. The precipitate was filtered off and dried, yielding 0.055 g (17%) of compound 10 (MP: 237 ° C.).

Example B7
Production of Compound 53

A mixture of intermediate 11 (0.0011 mol), 4-chloroquinoline (0.0012 mol) and 4N HCl / dioxane (0.0002 mol) in CH ₃ CN (2.5 ml) and EtOH (1 ml) at 18 ° C. Stir for hours, then cool to room temperature, pour into 10% aqueous K ₂ CO ₃ and extract with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was filtered off and dried, yielding 0.366 g (66%) of compound 53 (MP: 192 ° C.).

  Compound numbers 51, 52, 53 and 54 were prepared according to Example B7.

Example B8
Production of Compound 59

A solution of intermediate 14 (0.0005 mol) in 3N HCl (5 ml) and THF (1 ml) was stirred at 100 ° C. for 10 days. 10% aqueous K ₂ CO ₃ and CH ₂ Cl ₂ were added. The mixture was extracted. The organic layer was separated, dried (MgSO ₄ ), filtered off and concentrated. The residue (0.2 g) was purified by column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 93/7 / 0.1). The residue (0.010 g, 5%) was subjected to column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 93 /
7 / 0.7). The pure fractions were collected and the solvent was evaporated, yielding 0.003 g (1.5%) of compound 59.

Example B9
a) Production of Compound 1

Of intermediate 16 (0.0005 mol), 4-bromopyridine hydrochloride (1: 1) (0.0005 mol) and DIPEA (0.0004 mol) in CH ₃ CN (1.5 ml) and EtOH (0.5 ml). The mixture was stirred at 65 ° C. for 18 hours. 4N HCl (0.2 eq) and dioxane (29 μl) were added. The mixture was stirred at 65 ° C. for 18 hours, then cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.24 g) was purified by column chromatography over chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 93/7 / 0.5; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.039 g (19%) of compound 1 (MP: 186 ° C.).
b) Production of compound 2

Of intermediate 16 (0.0005 mol), 4-chloro-2-pyridinemethanol (0.0005 mol) and 4N HCl / dioxane (0.0001 mol) in CH ₃ CN (1.5 ml) and EtOH (0.5 ml). The mixture was stirred at 65 ° C. for 18 hours. 4N
HCl (2 eq) and dioxane (29 μl) were added. The mixture was stirred at 65 ° C. for 18 hours, then cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.18 g) was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 93/7 / 0.5; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.03g, 14%) was crystallized from _CH 3 CN / DIPE. The precipitate was filtered off and dried, yielding 0.03 g (9%) of compound 2 (MP: 163 ° C.).

Example B10
Production of Compound 55

A mixture of intermediate 18 (0.0008 mol) and 4-bromopyridine hydrochloride (1: 1) (0,0008 mol) in DIPEA (0.0006 mol), CH ₃ CN (2.5 ml) and EtOH (1 ml). Stir at 65 ° C. for 18 hours, then cool to room temperature, pour into 10% aqueous K ₂ CO ₃ and extract with CH ₂ Cl ₂ . The organic layer was decanted, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.357 g) column chromatography over silica gel _{(eluent: CH 2 Cl 2 / CH 3} OH / NH 4 OH 95/5 / 0.5; 15~40μm) was purified by. Pure fractions of solvent were evaporated to dryness. The residue (0.135 g) was crystallized from CH ₃ CN / EtOH / DIPE to give 0.126 g (35%) of compound 55 as the hydrochloride salt (.0.99 HCl, MP: 245 ° C.).

  Compound numbers 56, 57 and 58 were prepared according to Example B10.

Example B11
Production of compound 50

A mixture of intermediate 20 (0.001 mol), 4-bromopyridine hydrochloride (1: 1) (0.001 mol) and DIPEA (0.0008 mol) in CH ₃ CN (2.5 ml) and EtOH (1 ml). Stir at 65 ° C. for 18 hours, then cool to room temperature, pour into 10% aqueous K ₂ CO ₃ and extract with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.37 g) was purified by column chromatography on chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 98/2 / 0.2 to 88/12 / 1.2; 3.5 μm) Purified. The pure fractions were collected and the solvent was evaporated until dryness. The residue was crystallized from CH ₃ CN. The precipitate was filtered off and dried, yielding 0.095 g (23%) of compound 50 (MP: 241 ° C.).

Example B12
Preparation of compound 49

Intermediate 22 (0.0015 mol) and 4-chloro-6,7-dihydro-5H-cyclopenta [b] in 4N HCl / dioxane (0.0003 mol), CH ₃ CN (3 ml) and EtOH (1.2 ml) A mixture of pyridin-7-ol (0.0016 mol) was stirred at 65 ° C. for 18 hours, then cooled to room temperature, poured into 10% aqueous K ₂ CO ₃ solution and extracted with CH ₂ Cl ₂ . The organic layer was decanted, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.74 g) was purified by column chromatography over chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 100 to 93/7 / 0.7; 5 μm). The solvent was evaporated to dryness. The residue (0.445g) was crystallized from EtOH. The residue was filtered off and dried, yielding 0.244 g (36%) of compound 49 (MP: 123 ° C.).

  Compound nos. 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 48 were prepared according to Example B12.

Example B13
Production of Compound 6

A mixture of intermediate 24 (0.0008 mol) and 4-bromopyridine hydrochloride (1: 1) (0.0008 mol) in DMF (3 ml) was stirred at 105 ° C. for 1 hour and 30 minutes and then cooled to room temperature. and poured into _10% K 2 CO ₃ aqueous solution. The precipitate was filtered, washed several times with water and dissolved in CH ₂ Cl ₂ / CH ₃ OH (small amount). The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.38 g) was purified by column chromatography over chromasil (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 96/4 / 0.4 to 88/12 / 1.2; 5 μm). . The pure fractions were collected and the solvent was evaporated. The crude oil (0.09 g, 23%) was dissolved in isopropanol and cooled in an ice bath. 5N HCl / isopropanol (2 equivalents) was added. The precipitate was filtered off and dried, yielding 0.063g (16%) of compound 6, melting point: 166 ° C.

Example B14
Production of Compound 62

Lithium aluminum hydride in 1M THF (0.398 mol) was added in portions to a solution of intermediate 30 in THF at 5 ° C. The mixture was stirred at room temperature for 2 hours. Water was carefully added at 5 ° C. EtOAc was added. The reaction mixture was filtered through celite and extracted. The organic layer was separated, dried over MgSO ₄ , filtered and concentrated. The crude product (0.12 g) was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 95/5 / 0.5; 30 g 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.042 g of compound 62.

Example B15
Preparation of compounds 63 and 64

Intermediate 38 (0.92 mmol), 4-chloro-6,7-dihydro-5H-cyclopenta [b] pyridin-7-ol (1 mmol) in CH ₃ CN (10 ml), 4M hydrogen chloride in dioxane (46 μl) Was heated at 65 ° C. for 5 hours. 10% aqueous K ₂ CO ₃ and EtOAc were added. The reaction mixture was extracted and the organic layer was separated, dried over MgSO ₄ , filtered and evaporated. The residue (0.4 g) was purified by high performance liquid chromatography (Stability silica 5 μm 150 × 30.0 mm). Mobile phase (0.2% NH ₄ OH; gradient 98/2 to 88/12 CH ₂ Cl ₂ / CH ₃ OH) yielded 49 mg of compound 63 and 114 mg of compound 64.

C. Pharmacological Example A2780 cells are human ovarian cancer cells with wild type p53.

The ability of the compound to preserve p53 in A2780 cells was measured by the p53 enzyme-linked immunosorbent assay (ELISA). The p53 assay is a “sandwich” enzyme immunoassay that uses two polyclonal antibodies. A polyclonal antibody specific for p53 protein was immobilized on the surface of a plastic well. Any p53 present in the sample to be assayed can bind to the capture antibody. A biotinylated detector polyclonal antibody can also recognize the p53 protein and bind to any p53 carried by the capture antibody. The detector antibody is sequentially bound by horseradish peroxidase-conjugated streptavidin. Horseradish peroxidase catalyzes the conversion of the chromogenic substrate o-phenylenediamine, the intensity of which is proportional to the amount of p53 protein bound to the plate. The colored reaction product is quantified using a spectrophotometer. Quantification is achieved by generating a standard curve using known concentrations of purified recombinant HIS-labeled p53 protein (see Example C.1).

  The cellular activity of the compound of formula (I) was measured in A2780 tumor cells using a colorimetric assay for cytotoxicity or survival (see Example C.2).

C. 1 p53 ELISA
A2780 cells (ATCC) were cultured in RPMI 1640 supplemented with 10% fetal calf serum (FCS), 2 mM L-glutamine and gentamicin in a humidified incubator containing 5% CO ₂ at 37 ° C.

  A2780 cells were seeded at 20,000 cells per well in a 96 well plate, cultured for 24 hours, and treated with compounds at 37 ° C. in a humidified incubator for 16 hours. After incubation, the cells were washed once with phosphate buffered saline and 30 μl per well of low salt RIPA buffer (20 mM Tris, pH 7.0, 0.5 mM EDTA, 1% Nonidet P40, 0.5% DOC). , 0.05% SDS, 1 mM PMSF, 1 μg / ml aprotinin and 0.5 μ / ml leupeptin). Plates were placed on ice for 30 minutes to complete lysis. The p53 protein was detected in the lysate by using the sandwich ELISA described below.

High binding polystyrene EIA / RIA 96 well plates (Costar 9018) are coated with capture antibody pAb1801 (Abcam ab28-100) at a concentration of 1 μg / ml in 50 μl of coating buffer (0.1 M NaHCO ₃ pH 8.2) per well. did. The antibody was allowed to attach overnight at 4 ° C. The coated plate was washed once with phosphate buffered saline (PBS) /0.05% Tween 20 and 300 μl of blocking buffer (PBS, 1% bovine serum albumin (BSA)) for 2 hours at room temperature. The incubation period was added. Dilutions of purified recombinant HIS-labeled p53 protein ranging from 3 to 200 ng / ml were made with blocking buffer and used as standards.

Plates were washed twice with PBS / 0.05% Tween 20 and blocking buffer or standard was added at 80 μl / well. 20 μl of lysis buffer was added to the standard. Samples were added to other wells at 20 μl lysate / well. After overnight incubation at 4 ° C., the plates were washed twice with PBS / 0.05% Tween 20. A 100 μl aliquot of secondary polyclonal antibody p53 (FL-393) (Tebubio, sc-6243) at a concentration of 1 μg / ml in blocking buffer was added to each well and allowed to attach for 2 hours at room temperature. Plates were washed 3 times with PBS / 0.05% Tween 20. Detection antibody anti-rabbit HRP (sc-2004, Tebbio) at 0.04 μg / ml in PBS / 1% BSA was added and incubated for 1 hour at room temperature. Plates were washed 3 times with PBS / 0.05% Tween 20 and 100 μl substrate buffer was added (substrate buffer was 1 tablet 10 mg o-phenylenediamine (OPD) from Sigma and 125 μl 3% H Prepared immediately before use by adding ₂ O ₂ to 25 ml OPD buffer, ie 35 mM citric acid, 66 mM Na ₂ HPO ₄ , pH 5.6).
After 5-10 minutes, the color reaction was stopped by adding 50 μl of stop buffer (1 MH ₂ SO ₄ ) per well. Absorbance at a dual wavelength of 490/655 nm was measured using a Biorad microplate reader and the results were subsequently analyzed.

  For each experiment, a control (containing no drug) and a blank incubation (containing no cells or drugs) were performed simultaneously. Blank values were subtracted from all control and sample values. For each sample, the p53 value (in absorbance units) was expressed as a percentage of the p53 value present in the control. Percentage preservation above 140% was defined as significant. Herein, the effect of the test compound is expressed as the lowest dose (LAD) that gives a minimum of 140% of the value of p53 present in the control (see Table 3 below).

  In some of the experiments, the assay was adapted and used in a 384 well culture plate.

C. 2 Proliferation Assay Human U87MG glioma cells were cultured in DMEM medium supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate, 1.5 g / L sodium bicarbonate, 50 μg / ml gentamicin and 10% heat-inactivated fetal bovine serum. Cultured. (U87MG cells are human glioblastoma cells with wild-type p53. In this cell line, MDM2 tightly controls p53 expression).

  Human A2780 ovarian cancer cells are C. A kind gift from Dr. Hamilton (Fox Chase Cancer Center, Pennsylvania, USA). The cells were cultured in RPMI 1640 medium supplemented with 2 mM L-glutamine, 50 μg / ml gentamicin and 10% fetal calf serum.

Reagents used in the Alamar Blue assay Resazurin was purchased from Aldrich (product number 199303). Potassium ferrocyanide, potassium ferricyanide, KH ₂ PO ₄ and K ₂ HPO ₄ were purchased from Sigma (product numbers P9387, P8131, P5655 and P8281 respectively).

0.1M potassium phosphate buffer (PPB) was made as follows. That is, 2.72 grams of KH ₂ PO ₄ and 13.86 grams of K ₂ HPO ₄ were dissolved in 500 ml of milli-Q H ₂ O, the pH was adjusted to pH 7.4, and the volume was milli-Q H _The buffer was sterilized by filtration and stored at room temperature. Resazurin stock solution (PPB-A) was prepared fresh by dissolving 45 mg resazurin in 15 ml PBS. 30 mM potassium ferricyanide (PPB-B) was prepared by dissolving 0.987 grams of potassium ferricyanide in 100 ml PPB. 30 mM potassium ferrocyanide (PPB-C) was prepared by dissolving 1.266 grams of potassium ferrocyanide in 100 ml PPB.

  A mixture of PPB-A, PPB-B and PPB-C was prepared by mixing equal volumes of each solution. Resazurin working solution (referred to herein as “Alamar Blue” solution) is prepared by diluting the mixture 20 times (volume / volume) with PBS and filter sterilizing; It could be stored at 4 ° C for up to 2 weeks.

Alamar Blue Assay Procedure For experiments in 384-well culture plates, cells were plated in black Falcon 384-well culture plates with clear bottom (Life Technologies, Merelbeek, Belgium) at a density of 5 × 10 ³ cells / ml in 45 μl medium. Sowing. Cells were allowed to attach to plastic for 24 hours. The compound to be tested was prediluted (50 times in medium) and 5 μl of prediluted compound was added to the wells. After 4 days of incubation, 10 μl of Alamar Blue solution was added to each well and the cells were further incubated at 37 ° C. for 5 hours (A2780) or 6 hours (U87MG). The fluorescence intensity was measured for each well with a fluorescence plate reader (Fluorskan, Labsystems, 540 nm excitation and 590 nm measurement).

Anti-proliferative activity was calculated as the percentage of remaining viable cells at the treated conditions relative to the control (untreated cells) conditions. Within one experiment, the result for each experimental condition is the average of 3 replicate wells. When appropriate, experiments were repeated to establish a complete concentration-response curve. Where appropriate, IC ₅₀ values (concentration of drug required to reduce cell proliferation to 50% of control) were analyzed using probit analysis of graded data (Finney, DJ, Probit Analysis, 2nd edition). (Chapter 10, Graded Responses, Cambridge University Press, Cambridge 1962). Herein, the effect of the test compound is expressed as pIC ₅₀ (negative logarithm of the IC ₅₀ value) (see Table 4).

D. Analytical data
General Procedure for Liquid Chromatography (LC) LC measurements consist of a UPLC comprising a degassed binary pump, an autosampler, a diode array detector (DAD) and a column as specified in each of the methods below. Ultra High Performance Liquid Chromatography) is performed using an Acquity (Waters) apparatus and the column is kept at a temperature of 40 ° C. The flow from the column was brought to the MS detector. The MS detector was configured with an electrospray ionization source. The capillary needle voltage was 3 kV and the ionization source temperature was maintained at 130 ° C. with a Quattro (triple quadrupole mass spectrometer from Waters). Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

In addition to the general procedure above: Reversed phase UPLC is a Waters with a flow rate of 0.35 ml / min.
It was carried out on an Acquity BEH (crosslinked ethylsiloxane / silica hybrid) C18 column (1.7 μm, 2.1 × 100 mm). 3.5 minutes from 90% A and 10% B (hold for 0.5 minutes) using 2 mobile phases (mobile phase A: 95% 7 mM ammonium acetate / 5% acetonitrile; mobile phase B: 100% acetonitrile) Was carried out at a gradient condition of 8% A and 92% B for 2 minutes, and returned to the initial condition at 0.5 minutes and held for 1.5 minutes. An injection volume of 2 μl was used. The cone voltage was 20 V for positive and negative ionization modes. Mass spectra were acquired by scanning from 100 to 1000 in 0.2 seconds using a 0.1 second interscan delay.

E. Composition Example: Film-coated tablets Manufacture of tablet cores 100 g of a compound of formula (I), 570 g of lactose and 200 g of starch are thoroughly mixed and then 5 g of dodecyl in about 200 ml of water Humidify with a solution of sodium sulfate and 10 g of polyvinylpyrrolidone. The wet powder mixture is sieved, dried and sieved again. Thereafter, 100 g of crystalline cellulose and 15 g of hydrogenated vegetable oil are added. The whole is mixed well and compressed into tablets, yielding 10,000 tablets each containing 10 mg of the compound of formula (I).

Coating To a solution of 10 g methylcellulose in 75 ml denatured ethanol is added a solution of 5 g ethylcellulose in 150 ml dichloromethane. Then 75 ml dichloromethane and 2.5 ml 1,2,3-propanetriol are added. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the former, and then 2.5 g magnesium octadecanoate, 5 g polyvinylpyrrolidone and 30 ml concentrated pigment suspension are added and the whole is homogenized. The tablet core is coated with the mixture thus obtained in a coating apparatus.

Claims (15)

Formula (I), including any stereoisomers thereof:

[Where m is 0, is intended or One direct bond;
n is 0, 1, 2 or 3, and when n is 0, a direct bond is intended;
p is 0 or 1, and when p is 0, a direct bond is intended;
s is 0, it is intended or One direct bond;
t is 0 or 1, and when t is 0, a direct bond is intended;
X is C (═O) or CHR ⁸ , wherein R ⁸ is hydrogen; C _1-6 alkyl; C _3-7 cycloalkyl; —C (═O) —NR ¹⁷ R ¹⁸ ; carboxyl; aryl C _1-6 alkyloxycarbonyl; heteroaryl; heteroarylcarbonyl; heteroaryl _{C 1-6} alkyloxycarbonyl; piperazinylcarbonyl; pyrrolidinyl; _{piperidinylcarbonyl; C 1-6} alkyloxycarbonyl; hydroxy, amino, aryl and C _1-6 alkyl substituted with a substituent selected from heteroaryl; C _3-7 cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; hydroxy, hydroxy C _{1 -6} alkyl and hydroxy _{C 1-6} Arukiruoki C _1-6 piperazinylcarbonyl substituted with a substituent selected from alkyl; pyrrolidinyl substituted with a hydroxy _{C 1-6} alkyl; and _{hydroxy, C 1-6} alkyl, hydroxy _{C 1-6} alkyl, With 1 or 2 substituents selected from C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyl (dihydroxy) C _1-6 alkyl and C _1-6 alkyloxy (hydroxy) C _1-6 alkyl Selected from substituted piperidinylcarbonyl;
R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, di (C _1-6 alkyl) amino C _1-6 alkyl, aryl C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl, hydroxy Each independently selected from C _1-6 alkyl, hydroxy C _1-6 alkyl (C _1-6 alkyl) or hydroxy C _1-6 alkyl (aryl C _1-6 alkyl);

Is —CR ⁹ ═C <(and in that case the dotted line is a bond), —C (═O) —CH <, —CHR ⁹ —CH <or —CHR ⁹ —N <, and each R ⁹ is independently Hydrogen or C _1-6 alkyl, or R ⁹ together with one of R ² or R ²⁰ forms a direct bond ;
R ¹ is hydrogen; aryl; heteroaryl; C _1-6 alkyloxycarbonyl; C _1-12 alkyl; or hydroxy, aryl, heteroaryl, amino, C _1-6 alkyloxy, mono or di (C _1-6 Alkyl) amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C _1-6 alkylpiperazinyl, aryl C _1-6 alkylpiperazinyl, heteroaryl C _1-6 alkylpiperazinyl, C _3-7 cycloalkylpiperazinyl And C _1-12 alkyl substituted with 1 or 2 substituents independently selected from C _3-7 cycloalkylC _1-6 alkylpiperazinyl;
R ² and R ²⁰ are
Halo, hydroxy, cyano, nitro, carboxyl;
Polyhalo C _1-6 alkyl, polyhalo C _1-6 alkyloxy;
C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl, aryl, heteroaryl, aryl C _1-6 alkyl, heteroaryl C _1-6 alkyl, C _3-7 cycloalkyl C _1-6 alkyl , Morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C _1-6 alkyloxy, aryloxy, heteroaryloxy, C _1-6 alkylthio, arylthio, heteroarylthio, C _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, arylcarbonyl, _{heteroarylcarbonyl, C 1-6 alkyloxycarbonyl, C 3-7} cycloalkyloxycarbonyl, aryloxycarbonyl, _{heteroaryloxycarbonyl, C 1-6 alkylcarbonyloxy, C 3-7} cycloalkyl Ruboniruokishi, both arylcarbonyloxy or heteroarylcarbonyloxy (of the group, halo, hydroxy, cyano, nitro, carboxyl, amino, mono- or di _{(C 1-6} alkyl) _{amino, C 1-6} alkyl, polyhalo C _1-6 alkyl, aryl, _{heteroaryl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl, C 1-6} 1 piece or it on more than the chosen from alkyloxycarbonyl and _{C 1-6} alkylcarbonyloxy Optionally and independently substituted with substituents); and — (CH ₂ ) _w — (C (═O)) _y NR ²¹ R ^22, where w is 0, 1, 2, 3, 4, Direct binding is intended when 5 or 6 and w is 0;
if y is 0 or 1, and if y is 0, a direct bond is intended;
R ²¹ and R ²² are hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkylcarbonyl and aryl C _1-6 alkylcarbonyl (all of the above groups are halo, hydroxy, amino, mono or di _{(C 1-6} alkyl) _{amino, C 1-6} alkyl, polyhaloC _{C 1-6 alkyl,} optionally by _{C 1-6} alkyloxy, one or more than on substituent is selected from aryl and heteroaryl And are independently selected from each other);
Or, R ²¹ and R ²² together with the nitrogen to which they are attached form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, any of the above groups being C _1-6 alkyl, polyhalo C _1-6 One or more selected from alkyl, C _1-6 alkyloxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, aryl C _1-6 alkyl and heteroaryl C _1-6 alkyl optionally in the substituents on the following it is substituted and independently]
Are selected independently from each other;
Alternatively, R ² and R ²⁰ together with the phenyl ring to which they are attached, are halo, hydroxy, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhalo C _{1 -6} alkyl, or optionally by C _1-6 alkyloxy, one or more than on substituents each independently selected from aryl and heteroaryl to form a naphthalenyl group substituted;
Alternatively, R ² and R ^{20 taken} together are halo, hydroxy, amino, mono or di (C _1-6 alkyl) amino, C _1-6 alkyl, polyhaloC _1-6 alkyl, C _1-6 alkyl. oxy, optionally in one or more than on substituent is selected from aryl and heteroaryl is substituted, the formula - (CH 2) _b - in _[wherein b is 3,4 or 5] Forms a divalent group;
Alternatively, one of R ² or R ²⁰ is as defined above and the other of R ² or R ²⁰ together with R ⁹ forms a direct bond;
R ³ is _{hydrogen; C 1-6} alkyl; _{heteroaryl; C 3-7} cycloalkyl; or hydroxy; hydroxy, amino, _{C 1-6} alkyl substituted with a substituent selected from aryl and heteroaryl C _3-7 cycloalkyl substituted with a substituent selected from amino, aryl and heteroaryl;
R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, hydroxy C _1-6 alkyl, polyhalo C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy, amino, C _{2 -6} alkenyl or C _1-6 alkyloxy; or R ⁴ and R ^{5 taken} together form a divalent group selected from methylenedioxy or ethylenedioxy;
R ⁶ is hydrogen, C _1-6 alkyloxycarbonyl or C _1-6 alkyl;
when p is 1, R ⁷ is hydrogen, arylC _1-6 alkyl, hydroxy or heteroarylC _1-6 alkyl;
Z is

Wherein R ¹⁰ or R ¹¹ is hydrogen, halo, hydroxy, amino, C _1-6 alkyl, nitro, polyhaloC _1-6 alkyl, cyano, cyano C _1-6 alkyl, tetrazolo C _1-6 alkyl, aryl, heteroaryl, aryl C _1-6 alkyl, heteroaryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, heteroaryl (hydroxy) C _1-6 alkyl, arylcarbonyl, hetero Arylcarbonyl, C _1-6 alkylcarbonyl, aryl C _1-6 alkylcarbonyl, heteroaryl C _1-6 alkylcarbonyl, C _1-6 alkyloxy, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl (hydroxy ) _{C 1-6} alkyl, aryl _{C 1-6} alkyl Carboxymethyl _{C 1-6 alkyl, C 1-6} alkyloxy _{C 1-6} alkyloxy _{C 1-6 alkyl, C 1-6} alkylcarbonyloxy _{C 1-6 alkyl, C 1-6} alkyloxycarbonyl _{C 1-6} alkyl Oxy C _1-6 alkyl, hydroxy C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl C _2-6 alkenyl, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyl Oxycarbonyl, C _1-6 alkylcarbonyloxy, aminocarbonyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C _1-6 alkyl and — (CH ₂ ) _v — (C (= _{^{O)) r - (CHR 19}} ) are each independently selected from the ^{u -NR} 13 ^{R 14}
Where v is 0, 1, 2, 3, 4, 5 or 6 and when v is 0, a direct bond is intended;
r is 0 or 1, and when r is 0, a direct bond is intended;
u is 0, 1, 2, 3, 4, 5 or 6 and when u is 0, direct binding is intended;
R ¹⁹ is hydrogen or C _1-6 alkyl;
R ¹³ and R ¹⁴ are hydrogen; C _1-12 alkyl; C _1-6 alkylcarbonyl; C _1-6 alkylsulfonyl; aryl C _1-6 alkylcarbonyl; C _3-7 cycloalkyl; C _3-7 cycloalkyl Carbonyl; — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ ; substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl, C _1-6 alkyloxy, aryl or heteroaryl C _1-12 alkyl; or C substituted with a substituent selected from hydroxy, C _1-6 alkyloxy, aryl, amino, aryl C _1-6 alkyl, heteroaryl or heteroaryl C _1-6 alkyl _3-7 either each independently selected from cycloalkyl; there have R ¹³ and ^{R 14,} together with the nitrogen to which they are attached, a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or _{C 1-6} alkyl, aryl _{C 1-6} alkyl, aryl _{C 1-6} alkyloxycarbonyl Forming a piperazinyl substituted with a substituent selected from heteroaryl C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 cycloalkylC _1-6 alkyl; 2, 3, 4, 5 or 6, and when k is 0, a direct bond is intended;
R ¹⁵ and R ¹⁶ are hydrogen; C _1-12 alkyl; aryl C _1-6 alkyloxycarbonyl; C _3-7 cycloalkyl; substituent selected from hydroxy, C _1-6 alkyloxy, aryl and heteroaryl _{C 1-12} alkyl is substituted in; and _{hydroxy, C 1-6} alkyloxy, aryl, aryl _{C 1-6} alkyl, substituted with a substituent selected from heteroaryl and heteroaryl _{C 1-6} alkyl Each independently selected from C _3-7 cycloalkyl; or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached, morpholinyl, piperazinyl, or C _1-6 alkyloxycarbonyl Forming piperazinyl substituted with:
R ¹² is _{hydrogen; C 1-6 alkyl; C 3-7} cycloalkyl; or hydroxy; hydroxy, _{amino, C 1-6} alkyl substituted with a substituent selected from _{C 1-6} alkyloxy and aryl C _3-7 cycloalkyl substituted with a substituent selected from amino, aryl and C _1-6 alkyloxy;
Aryl is phenyl or naphthalenyl;
Each phenyl or naphthalenyl is optionally 1, 2 or 3 substituents independently selected from halo, hydroxy, C _1-6 alkyl, amino, polyhalo C _1-6 alkyl and C _1-6 alkyloxy, respectively. And each phenyl or naphthalenyl can optionally be substituted with a divalent group selected from methylenedioxy and ethylenedioxy;
Heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;
Each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl may optionally be halo, hydroxy, C _1-6 alkyl, amino, polyhaloC _1-6 alkyl, aryl, aryl C Can be substituted with 1, 2 or 3 substituents each independently selected from _1-6 alkyl or C _1-6 alkyloxy; or
Each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl may optionally be substituted with a divalent group selected from methylenedioxy or ethylenedioxy]
A compound of
Its N- oxy-de, its addition salt or solvate thereof. R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, polyhaloC _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy, amino or C _1-6 alkyloxy, or R ⁴ and R ⁵ together form a divalent group selected from methylenedioxy or ethylenedioxy;
The substituents wherein R ¹⁵ and R ¹⁶ are selected from hydrogen, C _1-6 alkyl, aryl C _1-6 alkyloxycarbonyl, C _3-7 cycloalkyl, hydroxy, C _1-6 alkyloxy, aryl and heteroaryl Substituted with a substituent selected from C _1-12 alkyl substituted with, and hydroxy, C _1-6 alkyloxy, aryl, aryl C _1-6 alkyl, heteroaryl and heteroaryl C _1-6 alkyl Each independently selected from C _3-7 cycloalkyl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached are morpholinyl, piperazinyl, or C _1-6 alkyloxycarbonyl Forming a substituted piperazinyl,
The compound of claim 1.

The compound of claim 2 , wherein —CR ⁹ ═C <(and in which case the dotted line is a bond), —CHR ⁹ —CH <or —CHR ⁹ —N <.

There is a dotted line bond when it and its a -CR 9 = ^{C <,} A compound according to claim 3. X is C (═O) or CHR ⁸ and R ⁸ is hydrogen; —C (═O) —NR ¹⁷ R ¹⁸ ; aryl C _1-6 alkyloxycarbonyl; C ₁ substituted with hydroxy _-6 alkyl; piperazinylcarbonyl substituted with hydroxy; hydroxy C _1-6 alkyl; hydroxy C _1-6 alkyloxy C _1-6 alkyl; pyrrolidinyl substituted with hydroxyl C _1-6 alkyl; or hydroxy C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyl (dihydroxy) C _1-6 alkyl or C _1-6 alkyloxy (hydroxy) C Piperidinylcarbonyl substituted with 1 or 2 substituents selected from _1-6 alkyl;
R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, di (C _1-6 alkyl) amino C _1-6 alkyl, aryl C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl or hydroxy Each independently selected from C _1-6 alkyl;

Is —CR ⁹ ═C <, —CHR ⁹ —CH <or —CHR ⁹ —N <;
R ¹ is hydrogen, _{heteroaryl, C 1-6 alkyloxycarbonyl, C 1-12} alkyl, or be a _{C 1-12} alkyl substituted with heteroaryl;
R ³ is hydrogen, C _1-6 alkyl or heteroaryl;
R ⁴ and R ⁵ are each independently hydrogen, halo, C _1-6 alkyl, cyano, cyano C _1-6 alkyl, hydroxy or C _1-6 alkyloxy;
when p is 1, R ⁷ is arylC _1-6 alkyl or hydroxy;
Z is (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8) and A group selected from (a-9);
R ¹⁰ or R ¹¹ is hydrogen, halo, hydroxy, amino, C _1-6 alkyl, nitro, polyhalo C _1-6 alkyl, cyano, cyano C _1-6 alkyl, tetrazolo C _1-6 alkyl, aryl, heteroaryl , Heteroaryl C _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, arylcarbonyl, C _1-6 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl (hydroxy) C _1-6 Alkyl, aryl C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkylcarbonyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl _{C 1-6} alkyloxy _{C 1-6} alkyl, hydroxy _{C 1-} Alkyloxy _{C 1-6 alkyl, C 1-6} alkyloxycarbonyl _{C 2-6 alkenyl, C 1-6} alkyloxy _{C 1-6 alkyl, C 1-6} alkyloxycarbonyl, aminocarbonyl, hydroxy _{C 1-6} alkyl , Amino C _1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C _1-6 alkyl and — (CH ₂ ) _v — (C (═O)) _r — (CHR ¹⁹ ) _u —NR ¹³ R ¹⁴ each independently selected Is;
v is 0 or 1;
u is 0 or 1;
R ¹² is hydrogen or C _1-6 alkyl;
R ¹³ and R ¹⁴ are hydrogen; C _1-12 alkyl; C _1-6 alkylcarbonyl; C _1-6 alkylsulfonyl; aryl C _1-6 alkylcarbonyl; C _3-7 cycloalkylcarbonyl; — (CH ₂ ) _k —NR ¹⁵ R ¹⁶ ; each independently selected from C _1-12 alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl or aryl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached are substituted with morpholinyl, pyrrolidinyl, piperazinyl, or a substituent selected from C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl Forming piperazinyl;
k is 2;
R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, C _1-6 alkyl or aryl C _1-6 alkyloxycarbonyl;
R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form morpholinyl or piperazinyl, or piperazinyl substituted with C _1-6 alkyloxycarbonyl;
Aryl is phenyl, or phenyl substituted with halo; and heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl or tetrazolyl is optionally C _1-6 Can be substituted with one substituent selected from alkyl, aryl or arylC _1-6 alkyl,
The compound according to claim 1 or 2. s is 0; t is 0; m is 0; p is 0; n is 1 or 2; R ¹ is hydrogen; R ³ is hydrogen; R ⁴ and R ⁵ is each independently hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, hydroxy C _1-6 alkyl, C _2-6 alkenyl; R ⁶ is hydrogen;

Is —CR ⁹ ═C <and the dotted line is a bond; R ⁹ is hydrogen or C _1-6 alkyl; X is CH ₂ ; Z is (a-1), (a-2 ) Or (a-4); R ¹⁰ and R ¹¹ are each independently selected from hydrogen, hydroxy and hydroxy C _1-6 alkyl;
The compound according to any one of claims 1, 3 to 4 . R ² and R ²⁰ are halo, cyano, polyhaloC _1-6 alkyl, C _1-6 alkyl, morpholinyl, C _1-6 alkyloxy, hydroxy C _1-6 alkyl, —NR ²¹ R ²² [where R ²¹ Are hydrogen and R ²² is C _1-6 alkylcarbonyl] each independently; or R ² and R ²⁰ together with the phenyl ring to which they are attached form a naphthalenyl group Or one of R ² or R ²⁰ is as defined above and the other of R ² or R ²⁰ together with R ⁹ forms a direct bond. The compound according to any one of 1 to 6 . The compound is any stereoisomer thereof;
Its N- oxy de encompasses its addition salt or solvate thereof, the following groups

2. The compound of claim 1 selected from. 9. A compound according to any one of claims 1 to 8 for use as a medicament. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claims 1 to 8 as an active ingredient. For the manufacture of pharmaceuticals, use of a compound according to any one of claims 1 to 8. Use of a compound according to any of claims 1 to 8 for the manufacture of a medicament for the treatment of cancer. Use according to claim 12 , wherein the cancer is breast cancer, colorectal cancer, non-small cell lung cancer or acute myeloid leukemia. A combination of an anticancer agent and the compound according to any one of claims 1 to 8 . a) reacting an intermediate of formula (IV) with an intermediate of formula (V) wherein W is a suitable leaving group.

(With variables as defined in claim 1)
b) reacting a compound of (I-b), a suitable solvent in the presence of lithium aluminum hydride, be converted into compounds of formula (I-a)

(With variables as defined in claim 1)
c) reacting a carboxaldehyde of formula (VI) with an intermediate of formula (VII)

(With variables as defined in claim 1)
d) reacting an intermediate of formula (IV) with a carboxaldehyde of formula HC (═O) Z to obtain a compound of formula (Ic)

(With variables as defined in claim 1)
e) formula the intermediate of (VIII), is reacted with lithium aluminum hydride in a suitable solvent, to give a compound of formula (I-d)

(With variables as defined in claim 1)
f) reacting a compound of formula (XXIV) with lithium aluminum hydride in a suitable solvent to obtain a compound of formula (Ie).

(With variables as defined in claim 1)
g) converting the intermediate of formula (XIX) in the presence of a strong acid in a suitable solvent to obtain a compound of formula (III).

(With variables as defined in claim 1)
h ) reacting an intermediate of formula (IV-c) with an intermediate of formula (V) wherein W is a suitable leaving group in a reaction inert solvent to give a compound of formula (III-a) To get

(With variables as defined in claim 1) or
i) Fischer indole synthesis starting from intermediates of formulas (XXII) and (XXIII) to obtain compounds of formula (III-b)

(With variables as defined in claim 1)
The method for producing a compound according to claim 1, wherein: